Synthesis of acyclic and cyclic amines using iron-catalyzed nitrene group transfer

ABSTRACT

The present invention provides novel synthetic methods for making acyclic secondary amines by reacting an azide with a compound bearing one or more C—H groups, catalyzed by a Fe II -dipyrromethene complex. The acyclic secondary amines are thought to be formed through an intermolecular nitrene transfer. Also provided herein are methods of synthesizing protected (e.g., Boc- or Fmoc-protected) cyclic secondary amines (e.g., 5-, 6-, and 7-membered cyclic secondary amines) by reacting an azide that bears one or more C—H groups, catalyzed by a Fe II -dipyrromethene complex. The protected cyclic secondary amines are thought to be formed through an intramolecular nitrene transfer and may be subsequently deprotected to yield cyclic secondary amines.

RELATED APPLICATIONS

The present application is a divisional of and claims priority under 35U.S.C. §120 to U.S. Ser. No. 14/770,217, filed Aug. 25, 2015, now issuedas U.S. Pat. No. 9,487,472, which is a national stage filing under 35U.S.C. §371 of international PCT application, PCT/US2014/018623, filedFeb. 26, 2014, which claims priority under 35 U.S.C. §119(e) to U.S.provisional patent application, U.S. Ser. No. 61/769,469, filed Feb. 26,2013, each of which is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant numberCHE-0955885 awarded by the National Science Foundation. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Introducing functionality into unactivated C—H bonds remains asignificant challenge both in the realm of complex molecule synthesis aswell as in the elaboration of simple hydrocarbon feedstocks intovalue-added commodity chemicals (Bergman, Nature 2007, 446, 391;Labinger et al., Nature 2002, 417, 507). A challenge to the developmentof a general and mild aliphatic C—H bond functionalization strategy isthe unreactive nature of the substrates themselves. Saturatedhydrocarbons are chemically inert due to the large C—H bond dissociationenergy (BDE, 93-105 kcal/mol) coupled with the energetic and spatialinaccessibility of the C—H bonding and antibonding orbitals. C—H bondactivation processes are only realized under forcing conditions(Labinger et al., Nature 2002, 417, 507) or when directingfunctionalities pre-organize a substrate to interact with transitionmetal based catalysts (Ryabov, Chem. Rev. 90, 403 (1990); Dick et al.,Tetrahedron 62, 2439 (2006)). Although the C—H bonds of unsaturatedsubstrates (e.g., aromatic and olefinic C—H bonds substrates) arestronger than their aliphatic counterparts (BDE>110 kcal/mol), theavailable π-electron system provides a handle to engage the transitionmetal catalyst prior to C—H bond activation; furthermore, the C—Hbonding orbitals are more exposed and thus exhibit greater reactivity.Although chemists have exploited these attributes en route to thefunctionalization of sp² C—H bonds, where oxidative addition andreductive elimination reaction pathways are operative (Cho et al.,Science 295, 305 (2002); Ishiyama et al., J. Am. Chem. Soc. 124, 390(2002)), the catalytic conversion of sp³ C—H bonds within saturatedhydrocarbon substrates to carbon-heteroatom bonds remains elusive.

Biological C—H bond functionalization is primarily performed byiron-containing enzymes that utilize dioxygen as the terminal oxidant. Akey structural element of the putative hydroxylation catalyst in bothheme (where iron is embedded in a porphyrin) and non-heme systems is atransiently formed terminal iron oxo species, typically thought toinvolve multiple bond character (iron-oxo) (Ortiz de Montellano; Ed.Cytochrome P450: Structure, Mechanism, and Biochemistry, 4th ed.; KluwerAcademic/Plenum Publishers: New York, 2005; Krebs et al., Acc. Chem.Res. 2007, 40, 484). The iron-oxo contains two electrons residing inFe—O π* orbitals [Fe(d_(xz), d_(yz))-O(p_(x),p_(y))], which result in aweakened Fe—O bond vector possessing radical character, and thus rendersthe entire unit a reactive functionality. As a consequence of thiselectronic configuration, the iron-oxo can activate substrate aliphaticC—H bonds via an H-atom abstraction mechanism and thereby circumvent theorbital spatial restrictions that hinder oxidative addition pathways.Subsequent substrate functionalization results from recombination of theorganic radical generated in the activation step with the open-shelliron-hydroxyl to produce an alcohol product with concomitant reductionof the iron species. Despite this mechanistic precedent (Groves et al.,Biochem. Biophys. Res. Commun. 81, 154 (1978), viable catalystsfashioned with these design principles are only now being discovered.Furthermore, the reactivity of this intermediate is believed to bedictated by its electronic structure (Decker et al., J. Am. Chem. Soc.2007, 129, 15938; Bernasconi et al., Eur. J. Inorg. Chem. 2007, 3023; Yeet al., Curr. Opin. Chem. Biol. 2009, 13, 89). In non-heme enzymes, foursuch Fe^(IV)(oxo) complexes have been characterized, and theirreactivity has been linked to a common electronic feature: namely ahigh-spin ground state (S=2) (Krebs et al., Acc. Chem. Res. 2007, 40,484).

The direct functionalization of C—H bonds based on a strategyexemplified by cytochrome P450 would be transformative in convertingubiquitous C—H bonds into functional group handles and would circumventthe traditional synthetic requirement for functional group exchange(King et al., Top. Organometallic Chem. 6, 205, (2004)). The electronicstructure of the cytochrome P450 reactive iron-oxo intermediate can be,in principle, be replicated with any metal-ligand multiple bond (Nugentet al., Metal-Ligand Multiple Bonds; Wiley: New York, N.Y., 1988), andwould constitute a general strategy for the conversion of unactivatedC—H bonds into a variety of C-heteroatom bond products. Indeed, metalstabilized carbene and nitrene transfer has garnered significantinterest using noble metal catalysts (Zalatan et al., Top. Curr. Chem.292, 347 (2010); Au et al., J. Am. Chem. Soc. 121, 9120 (1999); Davieset al., Nature 451, 417 (2008)). In contrast, late, first row-transitionmetal complexes are potentially ideal catalyst candidates but have beenless explored. Their high d-electron count and compressed ligand fields(compared to their second and third row analogues) favor population ofmetal-ligand antibonding orbitals leading to destabilization andreactivity akin to the cytochrome P450 iron-oxo intermediate (Badiei etal., Angew. Chem., Int. Ed. 47, 9961 (2008); Laskowski et al., J. Am.Chem. Soc. 133, 771 (2011); King et al., J. Am. Chem. Soc. 133, 4917(2011); Lyaskovskyy et al., J. Am. Chem. Soc. 133, 12264 (2011); Wieseet al., J. Am. Chem. Soc. 134, 10114 (2012)).

Parallel to the work targeted at iron-mediated hydroxylation chemistry,C—H bond amination (Müller et al., Chem. Rev. 2003, 103, 2905; Davies etal., Angew. Chem., Int. Ed. 2005, 44, 3518; Halfen, Curr. Org. Chem.2005, 9, 657; Cenini et al., Coord. Chem. Rev. 2006, 250, 1234. Davieset al., Nature 2008, 451, 417; Collet et al., Chem. Commun. 2009, 5061;Zalatan et al., J. Top. Curr. Chem. 2010, 292, 347) and olefinaziridination (Müller et al., Chem. Rev. 2003, 103, 2905; Halfen, Curr.Org. Chem. 2005, 9, 657; Tanner, Angew. Chem., Int. Ed. 1994, 33, 599;Osborn et al., Tetrahedron: Asymmetry 1997, 8, 1693; Sweeney, Chem. Soc.Rev. 2002, 31, 247) have been reported. The synthesis andcharacterization of Fe(imido) complexes as isoelectronic surrogates toFe(oxo) functionalities have been targeted in the pursuit of effectingviable catalytic delivery of the nitrene functional unit to a C—H bondor olefinic substrates. Iron imido complexes have now been characterizedin four oxidation states spanning a range of spin states (Fe^(II), S=0(Brown et al., J. Am. Chem. Soc. 2005, 127, 1913); Fe^(III), S=1/2, 1,3/2 (Brown et al., J. Am. Chem. Soc. 2003, 125, 322; Betley et al., J.Am. Chem. Soc. 2003, 125, 10782; Bart et al., J. Am. Chem. Soc. 2006,128, 5302; Lu et al., J. Am. Chem. Soc. 2007, 129, 4; Scepaniak et al.,Angew. Chem., Int. Ed. 2009, 48, 3158; Cowley et al., Inorg. Chem. 2010,49, 6172); Fe^(IV), S=1; (Verma et al., J. Am. Chem. Soc. 2000, 122,11013; Thomas et al., J. Am. Chem. Soc. 2006, 128, 4956; Nieto et al.,J. Am. Chem. Soc. 2008, 130, 2716); Fe(V), S=1/2 (Ni et al., Chem.Commun. 2008, 6045)) and have been shown to engage in group transfer tocarbon monoxide to produce isocyanates (Brown et al., J. Am. Chem. Soc.2003, 125, 322; Cowley et al., Chem. Commun. 2009, 1760) and toisocyanides to produce carbodiimides (Cowley et al., Chem. Commun. 2009,1760), undergo hydrogenation (Bart et al., J. Am. Chem. Soc. 2006, 128,5302), and perform H atom abstraction from C—H bonds (Cowley et al.,Inorg. Chim. Acta 2011, 369, 40-44; King et al, Inorg. Chem. 2009, 48,2361).

For example, it has been recently reported that a catalytic C—H bondamination of toluene yields secondary benzylamines through a transientlyformed, high-spin (S=2) iron imido complex (Scheme 1). See, e.g., Kinget al. (J. Am. Chem. Soc. 2011, 133, 4917-4923). Isolation andcharacterization of the reactive intermediate elucidated the uniqueelectronic structure of its high-spin iron-bound imido radical, whereina high-spin Fe(III) (S=5/2) is antiferromagnetically coupled to theimido radical (S=−1/2) to give a high-spin ground state. This electronicstructure places significant radical character on both the Fe—N σ and πbond vectors, facilitating both radical H-atom abstraction and radicalrecombination pathways to proceed. Furthermore, the amination catalyticcycle remains in the quintet spin state (S=5/2), making each step of thecatalytic cycle spin-allowed.

Also reported is the preparation of substituted aziridines through acatalytic C—H bond amination of styrene (Scheme 2). See, e.g., King etal. (J. Am. Chem. Soc. 2011, 133, 4917-4923).

Despite these efforts, a facile synthetic route to a wide range offunctionalized amines (e.g., acyclic and cyclic secondary amines) isstill in need.

SUMMARY OF THE INVENTION

The ability to selectively incorporate functionality into unactivatedC—H bonds represents a significant advance in chemical synthesis of arange of useful compounds, such as acyclic and cyclic amines. Suchamines are important building blocks for the synthesis of biologicallyactive natural products, pharmaceutical agents. Reported strategies forconstructing those amines, such as saturated heterocyclic amines, areheavily dependent on functional group exchange, leading to inefficientsynthetic protocols with poor atom economy and waste generation. Acatalyst capable of the direct amination of aliphatic C—H bonds may beemployed for a streamlined synthetic approach to those amines. One ofthe advantages of this method is its potential to harness saturatedhydrocarbon feedstocks. Unfortunately, current C—H bondfunctionalization protocols often require substrate preoxidation orstrong chemical oxidants (Zalatan et al., Top. Curr. Chem. 292, 347(2010)), which contribute to a lack of generality for this bondconstruction. The present invention provides a selective synthesis of avariety of acyclic and cyclic amines using iron-catalyzed nitrene grouptransfer into tertiary, secondary, and primary C—H bonds. The presentinvention not only provides the synthetic methodology to such amines butalso provide the catalysts, ligands, intermediates, and systems usefulin the inventive methodology. The iron-based catalysts used in theinventive methods are capable of functionalizing a broad range ofaliphatic C—H bonds to form the amines. This novel methodology providesaccess to acyclic and cyclic amines of various chain-lengths or ringsizes and of architectural diversity that will find significant utilityin, e.g., pharmaceutical and fine chemical synthesis.

In one aspect, the present invention provides methods of preparingacyclic secondary amines of Formula (I):

and salts and stereoisomers thereof, wherein R¹-R⁶ are as describedherein. The inventive methods comprise the steps of:

reacting an azide of Formula (A), or a salt or stereoisomer thereof,with a ferrous (Fe^(II)) compound of Formula (B) (aFe^(II)-dipyrromethene complex), or a salt or stereoisomer thereof, toprovide a ferric (Fe^(III)) compound of Formula (C) (aFe^(III)-dipyrromethene complex), or a salt or stereoisomer thereof:

and

reacting the ferric compound of Formula (C), or a salt or stereoisomerthereof, with a compound of Formula (D) or (E), or a salt orstereoisomer thereof, to provide a compound of Formula (I):

or a salt or stereoisomer thereof.

The inventive methods involve an iron-based catalyst, e.g., the ferrous(Fe^(II)) compound of Formula (B), that may leverage the reactivity ofthe iron-born metal-ligand multiple bonds to promote the directamination of the aliphatic C—H bonds of the compound of Formula (D) or(E), or a salt or stereoisomer thereof. Exposure of an organic azide(e.g., the compounds of Formula (A), or a salt or stereoisomer thereof)to the iron-based catalyst furnishes amines (e.g., the compound ofFormula (I), or a salt or stereoisomer thereof) that may bear complexcore-substitution patterns.

Another aspect of the present invention relates to methods of preparinga compound of Formula (II-1):

or a salt or stereoisomer thereof, the method comprising reacting anazide of Formula (F), or a salt or stereoisomer thereof, with a ferrouscompound of Formula (G) (a Fe^(II)-dipyrromethene complex), or a salt orstereoisomer thereof:

In another aspect, the method of preparing a compound of Formula (II-1),or a salt or stereoisomer thereof, further comprises reacting thecompound of Formula (II-1), or a salt or stereoisomer thereof, withBoc₂O to provide a compound of Formula (II-2-A):

or a salt or stereoisomer thereof.

In another aspect, the method of preparing a compound of Formula (II-1),or a salt or stereoisomer thereof, further comprises reacting thecompound of Formula (II-1), or a salt or stereoisomer thereof, withFmoc-OSuc to provide a compound of Formula (II-2-B), or a salt thereof:

or a salt or stereoisomer thereof.

In still another aspect, the method of preparing a compound of Formula(II-2-A) or (II-2-B), or a salt or stereoisomer thereof, furthercomprises deprotecting the compound of Formula (II-2-A) or (II-2-B), ora salt or stereoisomer thereof, to provide a cyclic amine of Formula(II-3):

or a salt or stereoisomer thereof.

Exemplary compounds that may be prepared using the inventive methodsinclude, but are not limited to:

and salts and stereoisomers thereof.

The present application refers to various issued patent, publishedpatent applications, journal articles, and other publications, all ofwhich are incorporated herein by reference.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Figures, the Examples, andthe Claims.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” as used herein, refers toheteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),isobutyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents. In certain embodiments, the alkyl group isunsubstituted C₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, thealkyl group is substituted C₁₋₁₀ alkyl.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining three heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group. In certain embodiments, the aralkyl isoptionally substituted benzyl. In certain embodiments, the aralkyl isbenzyl. In certain embodiments, the aralkyl is optionally substitutedphenethyl. In certain embodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 p electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. A “partially unsaturated” ring system is furtherintended to encompass rings having multiple sites of unsaturation, butis not intended to include aromatic groups (e.g., aryl or heteroarylgroups) as herein defined. Likewise, “saturated” refers to a group thatdoes not contain a double or triple bond, i.e., contains all singlebonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, which are divalent bridging groups arefurther referred to using the suffix -ene, e.g., alkylene, alkenylene,alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

As used herein, the term “optionally substituted” refers to optionallysubstituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —SCN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa),—ON(R^(bb))₂, —N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH,—SR^(aa), —SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂,—CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂,—OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—OC(═NR^(bb))N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa),—SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(cc))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —SCN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂,—SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂,—C(═O)SR^(cc), —C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(bb)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—SCN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—C(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl,C₁₋₆-perhaloalkyl, C₂₋₆ alkenyl, C₂₋₄ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —SCN, —NO₂,—N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₄ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₄ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(H)NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, —C(═S)NH(C₁₋₆ alkyl), —C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(X)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂,C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, C⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” as used herein refers to a moiety selected from the groupconsisting of —C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or—C(═S)SR^(aa), wherein R^(aa) and R^(bb) are as defined herein.

Nitrogen atoms can be optionally substituted as valency permits, andinclude primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —SCN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc), and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-1-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (or t-butyloxycarbonyl (BOC or Boc)),1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate(Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc),4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate,N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate(Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate,p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate,2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate(Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-pnitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, t-butyloxycarbonyl (BOC orBoc), alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate),benzylsulfonate, and tosylate (Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

“Adamantyl” or “Ad” refers to adamantane radical

“Mesityl” or “Mes” refers to 2,4,6-trimethylphenyl.

“Boc₂O” or “(BOC)₂O” refers to Boc anhydride or, in other words,di-t-butyl dicarbonate.

As used herein, the term “nitrene” refers to a compound that can berepresented by the general formula

wherein R^(N) is an atom or group including, but not limited to,hydrogen, halogen, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl. Anitrene is the nitrogen analog of a carbene. The nitrogen atom of anitrene has only six valence electrons and is, therefore, anelectrophile. In the most simple nitrene, the linear imidogen (HN:), twoof the six available electrons form a covalent bond with hydrogen, andtwo other create a free electron pair and the two remaining electronsoccupy two degenerate p orbitals. Because nitrenes are highly reactive,they are usually not isolated. Instead, they are formed as reactiveintermediates during a reaction. There are two common ways to generatenitrenes: (1) from azides by thermolysis or photolysis, with expulsionof nitrogen gas; and (2) from isocyanates, with expulsion of carbonmonoxide.

The term “amination” refers to a chemical reaction that involves theformation of one or more carbon-nitrogen bond, wherein the nitrogen istrivalent.

The term “catalysis” refers to the change in rate of a chemical reactiondue to the participation of a substance called a “catalyst.” Unlikeother reagents that participate in the chemical reaction, a catalyst isnot consumed by the reaction itself. A catalyst works by providing analternative reaction pathway to the reaction product. Catalyticreactions have a lower rate-limiting free energy of activation than thecorresponding uncatalyzed reaction, resulting in a higher reaction rateat the same temperature. A reaction is “catalyzed” when the addition ofa catalyst into the reaction increases the reaction rate of thereaction. Exemplary mechanistic explanations of catalysis include thatcatalysts may affect the reaction environment favorably, bind to thereagents to polarize bonds, form specific intermediates that are notproduced naturally, or cause lysis of reagents to reactive forms.Kinetically, catalytic reactions are typical chemical reactions; i.e.,the reaction rate depends on the frequency of contact of the reactantsin the rate-determining step. Usually, the catalyst participates in thisslowest step, and reaction rates are limited by the amount of catalystand its activity. Many transition metals and transition metal complexesas illustrated by the present invention are catalysts.

The term “Fmoc-OSuc” refers to 9-fluorenylmethyl N-succinimidylcarbonate or Fmoc-OSu.

As used herein, the terms “Fe^(II)” and “Fe(II)” are usedinterchangeably.

As used herein, the terms “Fe^(III)” and “Fe(III)” are usedinterchangeably.

These and other exemplary substituents are described in more detail inthe Detailed Description, Figures, Examples, and Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

OTHER DEFINITIONS

The following definitions are more general terms used throughout thepresent application:

As used herein, the term “salt” refers to ionic compounds that resultfrom the neutralization reaction of an acid and a base. A salt iscomposed of one or more cations (positively charged ions) and one ormore anions (negative ions) so that the salt is electrically neutral(without a net charge). Salts of the compounds of this invention includethose derived from inorganic and organic acids and bases. Examples ofacid addition salts are salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid, or malonic acid or by using other methods known in the art such asion exchange. Other salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Further saltsinclude ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate, and aryl sulfonate.

The term “tautomers” refer to compounds that are interchangeable formsof a particular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the acid- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female and at any stage of development. Anon-human animal may be a transgenic animal.

The terms “administer,” “administering,” or “administration,” as usedherein refers to implanting, absorbing, ingesting, injecting, inhaling,or otherwise introducing a compound (e.g., an acyclic or cyclic aminesynthesized using the methods of the invention), or a pharmaceuticalcomposition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a “pathological condition” (e.g., a disease, disorder, orcondition, or one or more signs or symptoms thereof) described herein.In some embodiments, treatment may be administered after one or moresigns or symptoms have developed or have been observed. In otherembodiments, treatment may be administered in the absence of signs orsymptoms of the disease or condition. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved, for example, to delay or prevent recurrence.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-D show exemplary X-ray crystal structures ofFe^(II)-dipyrromethene complexes useful in catalyzing C—H bond aminationreactions.

FIG. 2 illustrates a proposed mechanism of an intermolecular C—Hamination reaction catalyzed by Fe^(II)-dipyrromethene complex 3A toyield acyclic secondary amines.

FIG. 3 illustrates a proposed mechanism of an intramolecular C—Hamination reaction catalyzed by Fe^(II)-dipyrromethene complex 3A toyield cyclic amines.

FIGS. 4A-D are exemplary X-ray crystal structures of Fe^(III)Cl (cyclicamine)-dipyrromethene complexes.

FIGS. 5A-D are exemplary solid-state core structures of Fe^(III)Cl(cyclic amine)-dipyrromethene complexes. (A) (^(Ad)L)FeCl(2-C₂H₃—NHC₄H₇)8; (B) (^(Ad)L)FeCl(2-Ph-NHC₄H₇) 9; (C) (^(Ad)L)FeCl(2-Et-NHC₄H₇) 10;(D) (^(Ad)L)FeCl(2,2-Me₂-NHC₄H₇) 11. Thermal ellipsoids were set at the50% probability level. Average bond lengths (Å) for: Fe—N_(dipyrrin)2.046(3), 2.062(3); Fe—N3, 2.145(3); Fe—Cl, 2.266(4).

FIG. 6 shows a X-ray crystal structure of(S)-2-methyl-2-phenylpyrrolidine iron-bound adduct 20 obtained from areaction of (R)-2-phenyl-5-azidopentane (95% enantiomeric excess (ee))with stoichiometric quantities of compound 3A.

FIGS. 7A-C are exemplary solid-state core structures of Fe^(III)Cl(cyclic amine)-dipyrromethene complexes. (A) (^(Ad)L)FeCl(2-C₂H₃—NHC₅H₉)12; (B) (^(Ad)L)FeCl(2,2-Me₂-5,5-Me₂-NHC₅H₆) 21; (C)(^(Ad)L)FeCl(2,2-Me₂-4-(t-Bu)-NHC₃H₃) 22. Thermal ellipsoids were set atthe 50% probability level.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

A class of electrophilic complexes has been synthesized that are capableof mediating C—H bond functionalization through transiently-formed, ormetastable, transition states. Using dipyrromethene ligand platforms astruncated models of the porphyrin platform found in P450 hydroxylaseenzymes, it has been observed that the reactivity from theferrous-ligand constructs mirrors their porphyrin analogs. Illustratedin FIG. 1 are exemplary dipyrromethene ligand platforms that may beuseful in the present invention. All these Fe^(II)-dipyrromethenecomplexes show a high-spin state (S=2). Catalytic C—H bond (e.g., a sp³C—H bond) amination has been observed from the reaction of organicazides R—N₃ with Fe^(II) coordination complex 1 to form Fe^(III)(imido)complex 2 (Scheme 3). Shown in Table 1 are mass spectrometric dataindicating the formation of 2.

TABLE 1 Mass spectrometric data (TOF/ESI) of Fe^(III) (imido) complex 2.R Calculated m/z [M + H]⁺ Observed m/z [M + H]⁺ Ad 648.4318 648.4284t-Bu 570.3848 570.3851 Ph 590.3535 590.3509 Mes 632.4004 632.3965 Ts668.3310 668.3306

The iron-catalyzed amination reaction is useful with a variety oforganic azides and has shown reactivity with a range of organicsubstrates to form acyclic and cyclic secondary amines. For example,linear azides can be intramolecularly aminated to form pyrrolidine orpiperidine derivatives having an array of ring-substitutions, includingheteroatom-bearing functional groups. It is well known in the art thatthe azides employed in the inventive methods can be prepared using avariety of synthetic methods. For example, alkyl azides may be made byring-opening an epoxide using a nucleophilic compound (e.g., a Grignardreagent or alkyl lithium reagent) to afford a terminal alcohol, followedby conversion of the terminal alcohol to the corresponding azide. See,e.g., Corey et al., J. Am. Chem. Soc., 1992, 114, 1906-1908,incorporated herein by reference. Aryl azides may be prepared through acopper(II)-catalyzed conversion of organoboron compounds. See, e.g.,Grimes et al., Synthesis, 2010, 1441-1448, incorporated herein byreference. Acyl azides may be synthesized by reacting carboxylic acidswith trichloroacetonitrile, triphenylphosphine, and sodium azide. See,e.g., Kim et al., Synlett, 2008, 2072-2074, incorporated herein byreference.

Therefore, by iron-catalyzed nitrene group transfer into tertiary,secondary, and primary C—H bonds, a wide range of functionalizedproducts (e.g., acyclic and cyclic secondary amines) can be readilysynthesized. For example, acyclic secondary amines may be prepared by anintermolecular reaction of an azide with a C—H source, catalyzed by aFe^(II)-dipyrromethene complex, e.g., compound 3A shown in FIG. 1D.Cyclic secondary amines (e.g., 5-, 6-, and 7-membered cyclic secondaryamines) may be synthesized by an intramolecular reaction of an azidethat bears one or more C—H groups, catalyzed by a Fe^(II)-dipyrromethenecomplex, e.g., compound 3A (FIG. 1D). These reactions generate littlewaste and are useful in the synthesis of fine chemicals andpharmaceuticals.

Synthesis of Acyclic Secondary Amines

In one aspect, the present invention provides methods of preparingcompounds of Formula (I), which are acyclic secondary amines:

and salts and stereoisomers thereof, the method comprising the steps of:

reacting an azide of Formula (A), or a salt or stereoisomer thereof,with a ferrous compound of Formula (B), or a salt or stereoisomerthereof, to provide a ferric compound of Formula (C), or a salt orstereoisomer thereof:

reacting the ferric compound of Formula (C), or a salt or stereoisomerthereof, with a compound of Formula (D) or (E), or a salt orstereoisomer thereof, to provide a compound of Formula (I), or a salt orstereoisomer thereof:

wherein:

Z is selected from the group consisting of mesityl and2,6-dichlorophenyl;

R¹ is selected from the group consisting of optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

each one of R², R³, R⁴, R⁵, and R⁶ is independently selected from thegroup consisting of hydrogen, halogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a), —CN,—C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂, —NO₂,—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), —NR^(a)C(═O)N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), —OC(═O)N(R^(a))₂, and —ON(R^(a))₂;

optionally two of R², R³, R⁴, R⁵, and R⁶ groups are joined to form anoptionally substituted carbocyclyl or optionally substitutedheterocyclic ring;

each occurrence of R^(a) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, and a sulfur protecting group when attached to a sulfur atom, oroptionally two R^(a) groups are joined to form an optionally substitutedheterocyclic ring;

L is selected from the group consisting of N(R^(b))₃, R^(b)—O—R^(b),R^(b)—S—R^(b), optionally substituted heterocyclyl, and optionallysubstituted heteroaryl; and

each occurrence of R^(b) is independently selected from the groupconsisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl.

In compounds described herein, Z is selected from the group consistingof mesityl and 2,6-dichlorophenyl. In certain embodiments, Z is mesityl.In certain embodiments, Z is 2,6-dichlorophenyl.

In compounds of Formula (I), R¹ is a substituent on the nitrogen atom.In compounds of Formula (A), R¹ is a substituent on the azide group. Incertain embodiments, R¹ is substituted alkyl. In certain embodiments, R¹is unsubstituted alkyl. In certain embodiments, R¹ is C₁₋₆ alkyl. Incertain embodiments, R¹ is methyl. In certain embodiments, R¹ is ethyl.In certain embodiments, R¹ is propyl. In certain embodiments, R¹ isbutyl. In certain embodiments, R¹ is t-butyl. In certain embodiments, R¹is Ad. In certain embodiments, R¹ is substituted alkenyl. In certainembodiments, R¹ is unsubstituted alkenyl. In certain embodiments, R¹ isvinyl. In certain embodiments, R¹ is substituted alkynyl. In certainembodiments, R¹ is unsubstituted alkynyl. In certain embodiments, R¹ isethynyl. In certain embodiments, R¹ is substituted carbocyclyl. Incertain embodiments, R¹ is unsubstituted carbocyclyl. In certainembodiments, R¹ is cyclopropyl. In certain embodiments, R¹ iscyclobutyl. In certain embodiments, R¹ is cyclopentyl. In certainembodiments, R¹ is cyclohexyl. In certain embodiments, R¹ iscycloheptyl. In certain embodiments, R¹ is substituted heterocyclyl. Incertain embodiments, R¹ is unsubstituted heterocyclyl. In certainembodiments, R¹ is substituted aryl. In certain embodiments, R¹ isunsubstituted aryl. In certain embodiments, R¹ is substituted phenyl. Incertain embodiments, R¹ is tolyl. In certain embodiments, R¹ is 4-tolyl.In certain embodiments, R¹ is Mes. In certain embodiments, R¹ isunsubstituted phenyl. In certain embodiments, R¹ is substitutednaphthyl. In certain embodiments, R¹ is unsubstituted naphthyl. Incertain embodiments, R¹ is substituted heteroaryl. In certainembodiments, R¹ is unsubstituted heteroaryl. In certain embodiments, R¹is monocyclic heteroaryl. In certain embodiments, R¹ is 5-memberedmonocyclic heteroaryl. In certain embodiments, R¹ is 5-memberedmonocyclic heteroaryl, wherein only one of the five atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R¹ is 5-membered monocyclicheteroaryl, wherein only two of the five atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R¹ is 5-memberedmonocyclic heteroaryl, wherein only three of the five atoms in the ringof the heteroaryl are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, R¹ istetrazolyl. In certain embodiments, R¹ is 6-membered monocyclicheteroaryl. In certain embodiments, R¹ is 6-membered monocyclicheteroaryl, wherein only one of the six atoms in the ring of theheteroaryl is selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, R¹ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R¹ is triazinyl.In certain embodiments, R¹ is tetrazinyl. In certain embodiments, R¹ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R¹ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R¹ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R¹ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R¹ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R¹ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R¹ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R¹ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R¹ is—C(═NR^(a))R^(a). In certain embodiments, R¹ is —C(═NR^(a))OR^(a). Incertain embodiments, R¹ is —C(═NR^(a))N(R^(a))₂. In certain embodiments,R¹ is —C(═O)R^(a). In certain embodiments, R¹ is —C(═O)OR^(a). Incertain embodiments, R¹ is —C(═O)N(R^(a))₂. In certain embodiments, R¹is a nitrogen protecting group. In certain embodiments, R¹ is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

Compounds of Formulae (I), (D), and (E) each include a substituent R².In certain embodiments, R² is H. In certain embodiments, R² is halogen.In certain embodiments, R² is F. In certain embodiments, R² is Cl. Incertain embodiments, R² is Br. In certain embodiments, R² is I (iodine).In certain embodiments, R² is substituted acyl. In certain embodiments,R² is unsubstituted acyl. In certain embodiments, R² is —C(═O)R^(a). Incertain embodiments, R² is acetyl. In certain embodiments, R² is—C(═O)OR^(a). In certain embodiments, R² is —C(═O)N(R^(a))₂. In certainembodiments, R² is substituted alkyl. In certain embodiments, R² isunsubstituted alkyl. In certain embodiments, R² is C₁ alkyl. In certainembodiments, R² is methyl. In certain embodiments, R² is ethyl. Incertain embodiments, R² is propyl. In certain embodiments, R² is butyl.In certain embodiments, R² is Ad. In certain embodiments, R² issubstituted alkenyl. In certain embodiments, R² is unsubstitutedalkenyl. In certain embodiments, R² is vinyl. In certain embodiments, R²is substituted alkynyl. In certain embodiments, R² is unsubstitutedalkynyl. In certain embodiments, R² is ethynyl. In certain embodiments,R² is substituted carbocyclyl. In certain embodiments, R² isunsubstituted carbocyclyl. In certain embodiments, R² is cyclopropyl. Incertain embodiments, R² is cyclobutyl. In certain embodiments, R² iscyclopentyl. In certain embodiments, R² is cyclohexyl. In certainembodiments, R² is cycloheptyl. In certain embodiments, R² issubstituted heterocyclyl. In certain embodiments, R² is unsubstitutedheterocyclyl. In certain embodiments, R² is substituted aryl. In certainembodiments, R² is unsubstituted aryl. In certain embodiments, R² issubstituted phenyl. In certain embodiments, R² is unsubstituted phenyl.In certain embodiments, R² is substituted naphthyl. In certainembodiments, R² is unsubstituted naphthyl. In certain embodiments, R² issubstituted heteroaryl. In certain embodiments, R² is unsubstitutedheteroaryl. In certain embodiments, R² is monocyclic heteroaryl. Incertain embodiments, R² is 5-membered monocyclic heteroaryl. In certainembodiments, R² is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R²is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R²is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R² is tetrazolyl. In certain embodiments, R² is 6-memberedmonocyclic heteroaryl. In certain embodiments, R² is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R² is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R² is triazinyl.In certain embodiments, R² is tetrazinyl. In certain embodiments, R² isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R² is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R² is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R² is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R² is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R² is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R² is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R² is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R² is —OR^(a).In certain embodiments, R² is —OH when attached to an sp³ carbon atom.In certain embodiments, R² is —SR^(a). In certain embodiments, R² is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R² is—N(R^(a))₂. In certain embodiments, R² is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R² is —CN. In certain embodiments,R² is —SCN. In certain embodiments, R² is —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certain embodiments, R²is —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)N(R^(a))₂. In certainembodiments, R² is —NO₂. In certain embodiments, R² is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R² is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂. In certain embodiments, R² is —ON(R^(a))₂.

Compounds of Formulae (I), (D), and (E) each include a substituent R³.In certain embodiments, R³ is H. In certain embodiments, R³ is halogen.In certain embodiments, R³ is F. In certain embodiments, R³ is Cl. Incertain embodiments, R³ is Br. In certain embodiments, R³ is I (iodine).In certain embodiments, R³ is substituted acyl. In certain embodiments,R³ is unsubstituted acyl. In certain embodiments, R³ is —C(═O)R^(a). Incertain embodiments, R³ is acetyl. In certain embodiments, R³ is—C(═O)OR^(a), In certain embodiments, R³ is —C(═O)N(R^(a))₂. In certainembodiments, R³ is substituted alkyl. In certain embodiments, R³ isunsubstituted alkyl. In certain embodiments, R³ is C₁₋₆ alkyl. Incertain embodiments, R³ is methyl. In certain embodiments, R³ is ethyl.In certain embodiments, R³ is propyl. In certain embodiments, R³ isbutyl. In certain embodiments, R³ is Ad. In certain embodiments, R³ issubstituted alkenyl. In certain embodiments, R³ is unsubstitutedalkenyl. In certain embodiments, R³ is vinyl. In certain embodiments, R³is substituted alkynyl. In certain embodiments, R³ is unsubstitutedalkynyl. In certain embodiments, R³ is ethynyl. In certain embodiments,R³ is substituted carbocyclyl. In certain embodiments, R³ isunsubstituted carbocyclyl. In certain embodiments, R³ is cyclopropyl. Incertain embodiments, R³ is cyclobutyl. In certain embodiments, R³ iscyclopentyl. In certain embodiments, R³ is cyclohexyl. In certainembodiments, R³ is cycloheptyl. In certain embodiments, R³ issubstituted heterocyclyl. In certain embodiments, R³ is unsubstitutedheterocyclyl. In certain embodiments, R³ is substituted aryl. In certainembodiments, R³ is unsubstituted aryl. In certain embodiments, R³ issubstituted phenyl. In certain embodiments, R³ is unsubstituted phenyl.In certain embodiments, R³ is substituted naphthyl. In certainembodiments, R³ is unsubstituted naphthyl. In certain embodiments, R³ issubstituted heteroaryl. In certain embodiments, R³ is unsubstitutedheteroaryl. In certain embodiments, R³ is monocyclic heteroaryl. Incertain embodiments, R³ is 5-membered monocyclic heteroaryl. In certainembodiments, R³ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R³is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R³is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R³ is tetrazolyl. In certain embodiments, R³ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R³ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R³ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R³ is triazinyl.In certain embodiments, R³ is tetrazinyl. In certain embodiments, R³ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R³ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R³ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R³ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R³ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R³ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R³ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R³ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R³ is —OR^(a).In certain embodiments, R³ is —OH when attached to an sp³ carbon atom.In certain embodiments, R³ is —SR^(a). In certain embodiments, R³ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R³ is—N(R^(a))₂. In certain embodiments, R³ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R³ is —CN. In certain embodiments,R³ is —SCN. In certain embodiments, R³ is —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certain embodiments, R³is —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)N(R^(a))₂. In certainembodiments, R³ is —NO₂. In certain embodiments, R³ is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R³ is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂. In certain embodiments, R³ is —ON(R^(a))₂.

Compounds of Formulae (I), (D), and (E) each include a substituent R⁴.In certain embodiments, R⁴ is H. In certain embodiments, R⁴ is halogen.In certain embodiments, R⁴ is F. In certain embodiments, R⁴ is Cl. Incertain embodiments, R⁴ is Br. In certain embodiments, R⁴ is I (iodine).In certain embodiments, R⁴ is substituted acyl. In certain embodiments,R⁴ is unsubstituted acyl. In certain embodiments, R⁴ is —C(═O)R^(a). Incertain embodiments, R⁴ is acetyl. In certain embodiments, R⁴ is—C(═O)OR^(a). In certain embodiments, R⁴ is —C(═O)N(R^(a))₂. In certainembodiments, R⁴ is substituted alkyl. In certain embodiments, R⁴ isunsubstituted alkyl. In certain embodiments, R⁴ is C₁₋₆ alkyl. Incertain embodiments, R⁴ is methyl. In certain embodiments, R⁴ is ethyl.In certain embodiments, R⁴ is propyl. In certain embodiments, R⁴ isbutyl. In certain embodiments, R⁴ is Ad. In certain embodiments, R⁴ issubstituted alkenyl. In certain embodiments, R⁴ is unsubstitutedalkenyl. In certain embodiments, R⁴ is vinyl. In certain embodiments, R⁴is substituted alkynyl. In certain embodiments, R⁴ is unsubstitutedalkynyl. In certain embodiments, R⁴ is ethynyl. In certain embodiments,R⁴ is substituted carbocyclyl. In certain embodiments, R⁴ isunsubstituted carbocyclyl. In certain embodiments, R⁴ is cyclopropyl. Incertain embodiments, R⁴ is cyclobutyl. In certain embodiments, R⁴ iscyclopentyl. In certain embodiments, R⁴ is cyclohexyl. In certainembodiments, R⁴ is cycloheptyl. In certain embodiments, R⁴ issubstituted heterocyclyl. In certain embodiments, R⁴ is unsubstitutedheterocyclyl. In certain embodiments, R⁴ is substituted aryl. In certainembodiments, R⁴ is unsubstituted aryl. In certain embodiments, R⁴ issubstituted phenyl. In certain embodiments, R⁴ is unsubstituted phenyl.In certain embodiments, R⁴ is substituted naphthyl. In certainembodiments, R⁴ is unsubstituted naphthyl. In certain embodiments, R⁴ issubstituted heteroaryl. In certain embodiments, R⁴ is unsubstitutedheteroaryl. In certain embodiments, R⁴ is monocyclic heteroaryl. Incertain embodiments, R⁴ is 5-membered monocyclic heteroaryl. In certainembodiments, R⁴ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁴is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁴is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R⁴ is tetrazolyl. In certain embodiments, R⁴ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R⁴ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R⁴ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R⁴ is triazinyl.In certain embodiments, R⁴ is tetrazinyl. In certain embodiments, R⁴ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R⁴ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R⁴ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R⁴ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R⁴ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R⁴ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R⁴ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R⁴ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R⁴ is —OR^(a).In certain embodiments, R⁴ is —OH when attached to an sp³ carbon atom.In certain embodiments, R⁴ is —SR^(a). In certain embodiments, R⁴ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R⁴ is—N(R^(a))₂. In certain embodiments, R⁴ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R⁴ is —CN. In certain embodiments,R⁴ is —SCN. In certain embodiments, R⁴ is —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certain embodiments, R⁴is —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)N(R^(a))₂. In certainembodiments, R⁴ is —NO₂. In certain embodiments, R⁴ is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R⁴ is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂. In certain embodiments, R⁴ is —ON(R^(a))₂.

Compounds of Formulae (I), (D), and (E) each include a substituent R⁵.In certain embodiments, R⁵ is H. In certain embodiments, R⁵ is halogen.In certain embodiments, R⁵ is F. In certain embodiments, R⁵ is Cl. Incertain embodiments, R⁵ is Br. In certain embodiments, R⁵ is I (iodine).In certain embodiments, R⁵ is substituted acyl. In certain embodiments,R⁵ is unsubstituted acyl. In certain embodiments, R⁵ is —C(═O)R^(a). Incertain embodiments, R⁵ is acetyl. In certain embodiments, R⁵ is—C(═O)OR^(a). In certain embodiments, R⁵ is —C(═O)N(R^(a))₂. In certainembodiments, R⁵ is substituted alkyl. In certain embodiments, R⁵ isunsubstituted alkyl. In certain embodiments, R⁵ is C₁₋₆ alkyl. Incertain embodiments, R⁵ is methyl. In certain embodiments, R⁵ is ethyl.In certain embodiments, R⁵ is propyl. In certain embodiments, R⁵ isbutyl. In certain embodiments, R⁵ is Ad. In certain embodiments, R⁵ issubstituted alkenyl. In certain embodiments, R⁵ is unsubstitutedalkenyl. In certain embodiments, R⁵ is vinyl. In certain embodiments, R⁵is substituted alkynyl. In certain embodiments, R⁵ is unsubstitutedalkynyl. In certain embodiments, R⁵ is ethynyl. In certain embodiments,R⁵ is substituted carbocyclyl. In certain embodiments, R⁵ isunsubstituted carbocyclyl. In certain embodiments, R⁵ is cyclopropyl. Incertain embodiments, R⁵ is cyclobutyl. In certain embodiments, R⁵ iscyclopentyl. In certain embodiments, R⁵ is cyclohexyl. In certainembodiments, R⁵ is cycloheptyl. In certain embodiments, R⁵ issubstituted heterocyclyl. In certain embodiments, R⁵ is unsubstitutedheterocyclyl. In certain embodiments, R⁵ is substituted aryl. In certainembodiments, R⁵ is unsubstituted aryl. In certain embodiments, R⁵ issubstituted phenyl. In certain embodiments, R⁵ is unsubstituted phenyl.In certain embodiments, R⁵ is substituted naphthyl. In certainembodiments, R⁵ is unsubstituted naphthyl. In certain embodiments, R⁵ issubstituted heteroaryl. In certain embodiments, R⁵ is unsubstitutedheteroaryl. In certain embodiments, R⁵ is monocyclic heteroaryl. Incertain embodiments, R⁵ is 5-membered monocyclic heteroaryl. In certainembodiments, R⁵ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁵is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁵is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R⁵ is tetrazolyl. In certain embodiments, R⁵ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R⁵ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R⁵ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R⁵ is triazinyl.In certain embodiments, R⁵ is tetrazinyl. In certain embodiments, R⁵ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R⁵ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R⁵ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R⁵ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R⁵ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R⁵ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R⁵ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R⁵ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R⁵ is —OR^(a).In certain embodiments, R⁵ is —OH when attached to an sp³ carbon atom.In certain embodiments, R⁵ is —SR^(a). In certain embodiments, R⁵ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R⁵ is—N(R^(a))₂. In certain embodiments, R⁵ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R⁵ is —CN. In certain embodiments,R⁵ is —SCN. In certain embodiments, R⁵ is —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certain embodiments, R⁵is —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)N(R^(a))₂. In certainembodiments, R⁵ is —NO₂. In certain embodiments, R⁵ is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R⁵ is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂. In certain embodiments, R⁵ is —ON(R^(a))₂.

Compounds of Formulae (I), (D), and (E) each include a substituent R⁶.In certain embodiments, R⁶ is H. In certain embodiments, R⁶ is halogen.In certain embodiments, R⁶ is F. In certain embodiments, R⁶ is Cl. Incertain embodiments, R⁶ is Br. In certain embodiments, R⁶ is I (iodine).In certain embodiments, R⁶ is substituted acyl. In certain embodiments,R⁶ is unsubstituted acyl. In certain embodiments, R⁶ is —C(═O)R^(a). Incertain embodiments, R⁶ is acetyl. In certain embodiments, R⁶ is—C(═O)OR^(a). In certain embodiments, R⁶ is —C(═O)N(R^(a))₂. In certainembodiments, R⁶ is substituted alkyl. In certain embodiments, R⁶ isunsubstituted alkyl. In certain embodiments, R⁶ is C₁₋₆ alkyl. Incertain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is ethyl.In certain embodiments, R⁶ is propyl. In certain embodiments, R⁶ isbutyl. In certain embodiments, R⁶ is Ad. In certain embodiments, R⁶ issubstituted alkenyl. In certain embodiments, R⁶ is unsubstitutedalkenyl. In certain embodiments, R⁶ is vinyl. In certain embodiments, R⁶is substituted alkynyl. In certain embodiments, R⁶ is unsubstitutedalkynyl. In certain embodiments, R⁶ is ethynyl. In certain embodiments,R⁶ is substituted carbocyclyl. In certain embodiments, R⁶ isunsubstituted carbocyclyl. In certain embodiments, R⁶ is cyclopropyl. Incertain embodiments, R⁶ is cyclobutyl. In certain embodiments, R⁶ iscyclopentyl. In certain embodiments, R⁶ is cyclohexyl. In certainembodiments, R⁶ is cycloheptyl. In certain embodiments, R⁶ issubstituted heterocyclyl. In certain embodiments, R⁶ is unsubstitutedheterocyclyl. In certain embodiments, R⁶ is substituted aryl. In certainembodiments, R⁶ is unsubstituted aryl. In certain embodiments, R⁶ issubstituted phenyl. In certain embodiments, R⁶ is unsubstituted phenyl.In certain embodiments, R⁶ is substituted naphthyl. In certainembodiments, R⁶ is unsubstituted naphthyl. In certain embodiments, R⁶ issubstituted heteroaryl. In certain embodiments, R⁶ is unsubstitutedheteroaryl. In certain embodiments, R⁶ is monocyclic heteroaryl. Incertain embodiments, R⁶ is 5-membered monocyclic heteroaryl. In certainembodiments, R⁶ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁶is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁶is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R⁶ is tetrazolyl. In certain embodiments, R⁶ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R⁶ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R⁶ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R⁶ is triazinyl.In certain embodiments, R⁶ is tetrazinyl. In certain embodiments, R⁶ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R⁶ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R⁶ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R⁶ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R⁶ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R⁶ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R⁶ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R⁶ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R⁶ is —OR^(a).In certain embodiments, R⁶ is —OH when attached to an sp³ carbon atom.In certain embodiments, R⁶ is —SR^(a). In certain embodiments, R⁶ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R⁶ is—N(R^(a))₂. In certain embodiments, R⁶ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R⁶ is —CN. In certain embodiments,R⁶ is —SCN. In certain embodiments, R⁶ is —C(═NR^(a))R^(a),—C(═NR^(a))OR^(a), or —C(═NR^(a))N(R^(a))₂. In certain embodiments, R⁶is —C(═O)R^(a), —C(═O)OR^(a), or —C(═O)N(R^(a))₂. In certainembodiments, R⁶ is —NO₂. In certain embodiments, R⁶ is—NR^(a)C(═O)R^(a), —NR^(a)C(═O)OR^(a), or —NR^(a)C(═O)N(R^(a))₂. Incertain embodiments, R⁶ is —OC(═O)R^(a), —OC(═O)OR^(a), or—OC(═O)N(R^(a))₂. In certain embodiments, R⁶ is —ON(R^(a))₂.

In certain embodiments, at least one R^(a) is H. In certain embodiments,at least one R^(a) is substituted acyl. In certain embodiments, at leastone R^(a) is unsubstituted acyl. In certain embodiments, at least oneR^(a) is acetyl. In certain embodiments, at least one R^(a) issubstituted alkyl. In certain embodiments, at least one R^(a) isunsubstituted alkyl. In certain embodiments, at least one R^(a) is C₁₋₆alkyl. In certain embodiments, at least one R^(a) is methyl. In certainembodiments, at least one R^(a) is ethyl. In certain embodiments, atleast one R^(a) is propyl. In certain embodiments, at least one R^(a) isbutyl. In certain embodiments, at least one R^(a) is substitutedalkenyl. In certain embodiments, at least one R^(a) is unsubstitutedalkenyl. In certain embodiments, at least one R^(a) is vinyl. In certainembodiments, at least one R^(a) is substituted alkynyl. In certainembodiments, at least one R^(a) is unsubstituted alkynyl. In certainembodiments, at least one R^(a) is ethynyl. In certain embodiments, atleast one R^(a) is substituted carbocyclyl. In certain embodiments, atleast one R^(a) is unsubstituted carbocyclyl. In certain embodiments, atleast one R^(a) is cyclopropyl. In certain embodiments, at least oneR^(a) is cyclobutyl. In certain embodiments, at least one R^(a) iscyclopentyl. In certain embodiments, at least one R^(a) is cyclohexyl.In certain embodiments, at least one R^(a) is cycloheptyl. In certainembodiments, at least one R^(a) is substituted heterocyclyl. In certainembodiments, at least one R^(a) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(a) is substituted aryl. In certainembodiments, at least one R^(a) is unsubstituted aryl. In certainembodiments, at least one R^(a) is substituted phenyl. In certainembodiments, at least one R^(a) is unsubstituted phenyl. In certainembodiments, at least one R^(a) is substituted heteroaryl. In certainembodiments, at least one R^(a) is unsubstituted heteroaryl. In certainembodiments, at least one R^(a) is substituted pyridyl. In certainembodiments, at least one R^(a) is unsubstituted pyridyl. In certainembodiments, at least one R^(a) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, at least one R^(a)is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts whenattached to a nitrogen atom. In certain embodiments, at least one R^(a)is an oxygen protecting group when attached to an oxygen atom. Incertain embodiments, at least one R^(a) is silyl, TBDPS, TBDMS, TIPS,TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl whenattached to an oxygen atom. In certain embodiments, two R^(a) groups arejoined to form a substituted heterocyclic ring. In certain embodiments,two R^(a) groups are joined to form an unsubstituted heterocyclic ring.In certain embodiments, two R^(a) groups are joined to form asubstituted heteroaryl ring. In certain embodiments, two R^(a) groupsare joined to form an unsubstituted heteroaryl ring. In certainembodiments, —OR^(a) is not —OH when —OR^(a) is attached to a carbonatom of a C═C bond. In certain embodiments, —N(R^(a))₂ is not —NH₂ when—N(R^(a))₂ is attached to a carbon atom of a C═C bond. In certainembodiments, —SR^(a) is not —SH when —SR^(a) is attached to a carbonatom of a C═C bond.

In compounds of Formulae (I), (D), and (E), any two of R², R³, R⁴, R⁵,and R⁶ groups may be joined to form a optionally substituted carbocyclylring or optionally substituted heterocyclic ring. In certainembodiments, R² and R³ are joined to form a optionally substitutedcarbocyclyl ring. In certain embodiments, R² and R³ are joined to form aoptionally substituted heterocyclic ring. In certain embodiments, R² andR⁴ are joined to form a optionally substituted carbocyclyl ring. Incertain embodiments, R² and R⁴ are joined to form a optionallysubstituted heterocyclic ring. In certain embodiments, R² and R⁵ arejoined to form a optionally substituted carbocyclyl ring. In certainembodiments, R² and R⁵ are joined to form a optionally substitutedheterocyclic ring. In certain embodiments, R² and R⁶ are joined to forma optionally substituted carbocyclyl ring. In certain embodiments, R²and R⁶ are joined to form a optionally substituted heterocyclic ring. Incertain embodiments, R³ and R⁴ are joined to form a optionallysubstituted carbocyclyl ring. In certain embodiments, R³ and R⁴ arejoined to form a optionally substituted heterocyclic ring. In certainembodiments, R³ and R⁵ are joined to form a optionally substitutedcarbocyclyl ring. In certain embodiments, R³ and R⁵ are joined to form aoptionally substituted heterocyclic ring. In certain embodiments, R³ andR⁶ are joined to form a optionally substituted carbocyclyl ring. Incertain embodiments, R³ and R⁶ are joined to form a optionallysubstituted heterocyclic ring. In certain embodiments, R⁴ and R⁵ arejoined to form a optionally substituted carbocyclyl ring. In certainembodiments, R⁴ and R⁵ are joined to form a optionally substitutedheterocyclic ring. In certain embodiments, R⁴ and R⁶ are joined to forma optionally substituted carbocyclyl ring. In certain embodiments, R⁴and R⁶ are joined to form a optionally substituted heterocyclic ring. Incertain embodiments, R⁵ and R⁶ are joined to form a optionallysubstituted carbocyclyl ring. In certain embodiments, R⁵ and R⁶ arejoined to form a optionally substituted heterocyclic ring.

In compounds of Formulae (I), (D), and (E)

represents a single bond with any stereochemistry (e.g., geometricisomer). In certain embodiments, in compounds of Formulae (I) and (D),R⁴ is cis to R⁵ and trans to R⁶. In certain embodiments, in compounds ofFormulae (I) and (D), R⁴ is trans to R⁵ and cis to R⁶. In certainembodiments, in compounds of Formula (E), R⁴ is cis to R² and trans toR³. In certain embodiments, in compounds of Formula (E), R⁴ is trans toR² and cis to R³.

In certain embodiments, R² and R³ are each hydrogen. In certainembodiments, R² and R³ are each hydrogen; and R⁵ or R⁶ is optionallysubstituted alkyl. In certain embodiments, R² and R³ are each hydrogen;and R⁵ or R⁶ is C₁₋₁₂ alkyl. In certain embodiments, R² and R³ are eachhydrogen; and R⁵ or R⁶ is C₁₋₆ alkyl. In certain embodiments, R² and R³are each hydrogen; and R⁵ or R⁶ is optionally substituted aryl. Incertain embodiments, R² and R³ are each hydrogen; and R⁵ or R⁶ isoptionally substituted phenyl. In certain embodiments, R² and R³ areeach hydrogen; and R⁵ or R⁶ is phenyl.

In certain embodiments, R², R³, and R⁴ are each hydrogen. In certainembodiments, R², R³, and R⁴ are each hydrogen; and R⁵ or R⁶ isoptionally substituted alkyl. In certain embodiments, R², R³, and R⁴ areeach hydrogen; and R⁵ or R⁶ is C₁₋₁₂ alkyl. In certain embodiments, R²,R³, and R⁴ are each hydrogen; and R⁵ or R⁶ is C₁₋₆ alkyl. In certainembodiments, R², R³, and R⁴ are each hydrogen; and R⁵ or R⁶ isoptionally substituted aryl. In certain embodiments, R², R³, and R⁴ areeach hydrogen; and R⁵ or R⁶ is optionally substituted phenyl. In certainembodiments, R², R³, and R⁴ are each hydrogen; and R⁵ or R⁶ is phenyl.

In certain embodiments, R², R³, R⁴, and R⁵ are each hydrogen. In certainembodiments, R², R³, R⁴, and R⁵ are each hydrogen; and R⁶ is optionallysubstituted alkyl. In certain embodiments, R², R³, R⁴, and R⁵ are eachhydrogen; and R⁶ is C₁₋₁₂ alkyl. In certain embodiments, R², R³, R⁴, andR⁵ are each hydrogen; and R⁶ is C₁₋₆ alkyl. In certain embodiments, R²,R³, R⁴, and R⁵ are each hydrogen; and R⁶ is optionally substitutedalkenyl. In certain embodiments, R², R³, R⁴, and R⁵ are each hydrogen;and R⁶ is C₁₋₁₂ alkenyl. In certain embodiments, R², R³, R⁴, and R⁵ areeach hydrogen; and R⁶ is C₁₋₆ alkenyl. In certain embodiments, R², R³,R⁴, and R⁵ are each hydrogen; and R⁶ is optionally substituted alkynyl.In certain embodiments, R², R³, R⁴, and R⁵ are each hydrogen; and R⁶ isC₁₋₁₂ alkynyl. In certain embodiments, R², R³, R⁴, and R⁵ are eachhydrogen; and R⁶ is C₁₋₆ alkynyl. In certain embodiments, R², R³, R⁴,and R⁵ are each hydrogen; and R⁶ is optionally substituted aryl. Incertain embodiments, R², R³, R⁴, and R⁵ are each hydrogen; and R⁶ isoptionally substituted phenyl. In certain embodiments, R², R³, R⁴, andR⁵ are each hydrogen; and R⁶ is phenyl. In certain embodiments, R², R³,R⁴, and R⁵ are each hydrogen; and R⁶ is optionally substitutedheteroaryl.

In certain embodiments, R², R³, R⁴, and R⁶ are each hydrogen. In certainembodiments, R², R³, R⁴, and R⁶ are each hydrogen; and R⁵ is optionallysubstituted alkyl. In certain embodiments, R², R³, R⁴, and R⁶ are eachhydrogen; and R⁵ is C₁₋₁₂ alkyl. In certain embodiments, R², R³, R⁴, andR⁶ are each hydrogen; and R⁵ is C₁₋₆ alkyl. In certain embodiments, R²,R³, R⁴, and R⁶ are each hydrogen; and R⁵ is optionally substituted aryl.In certain embodiments, R², R³, R⁴, and R⁶ are each hydrogen; and R⁵ isoptionally substituted phenyl. In certain embodiments, R², R³, R⁴, andR⁶ are each hydrogen; and R⁵ is phenyl.

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

In certain embodiments, the compound of Formula (D) is of the formula:

and the compound of the Formula (I) is of the formula:

Compounds of Formula (B) include a ligand L attached to the Fe^(II)atom. L may be any ligand capable of binding to the Fe^(II) atom to forma coordination complex. In certain embodiments, L is a compoundincluding one or more electron donating moieties. In certainembodiments, L a compound including one or more heteroatoms. In certainembodiments, L is a solvent. In certain embodiments, L is N(R^(b))₃. Incertain embodiments, L is NEt₃. In certain embodiments, L is (i-Pr)₂NEt.In certain embodiments, L is R^(b)—O—R^(b). In certain embodiments, L isR^(b)—O—R^(b); and each occurrence of R^(b) is independently optionallysubstituted alkyl. In certain embodiments, L is R^(b)—O—R^(b); and eachoccurrence of R^(b) is independently C₁₋₆ alkyl. In certain embodiments,L is diethyl ether. In certain embodiments, L is methyl t-butyl ether.In certain embodiments, L is R^(b)—S—R^(b). In certain embodiments, L isdimethyl sulfide. In certain embodiments, L is diethyl sulfide. Incertain embodiments, L is substituted heterocyclyl. In certainembodiments, L is unsubstituted heterocyclyl. In certain embodiments, Lis substituted tetrahydrofuran. In certain embodiments, L is2-methyltetrahydrofuran. In certain embodiments, L is unsubstitutedtetrahydrofuran. In certain embodiments, L is substitutedtetrahydropyran. In certain embodiments, L is unsubstitutedtetrahydropyran. In certain embodiments, L is substituted heteroaryl. Incertain embodiments, L is unsubstituted heteroaryl. In certainembodiments, L is substituted pyridine. In certain embodiments, L is2,6-lutidine. In certain embodiments, L is unsubstituted pyridine.

In certain embodiments, at least one R^(b) is substituted alkyl. Incertain embodiments, at least one R^(b) is unsubstituted alkyl. Incertain embodiments, at least one R^(b) is C₁₋₆ alkyl. In certainembodiments, at least one R^(b) is methyl. In certain embodiments, atleast one R^(b) is ethyl. In certain embodiments, at least one R^(b) ispropyl. In certain embodiments, at least one R^(b) is butyl. In certainembodiments, at least one R^(b) is Ad. In certain embodiments, at leastone R^(b) is substituted alkenyl. In certain embodiments, at least oneR^(b) is unsubstituted alkenyl. In certain embodiments, at least oneR^(b) is vinyl. In certain embodiments, at least one R^(b) issubstituted alkynyl. In certain embodiments, at least one R^(b) isunsubstituted alkynyl. In certain embodiments, at least one R^(b) isethynyl. In certain embodiments, at least one R^(b) is substitutedcarbocyclyl. In certain embodiments, at least one R^(b) is unsubstitutedcarbocyclyl. In certain embodiments, at least one R^(b) is cyclopropyl.In certain embodiments, at least one R^(b) is cyclobutyl. In certainembodiments, at least one R^(b) is cyclopentyl. In certain embodiments,at least one R^(b) is cyclohexyl. In certain embodiments, at least oneR^(b) is cycloheptyl. In certain embodiments, at least one R^(b) issubstituted heterocyclyl. In certain embodiments, at least one R^(b) isunsubstituted heterocyclyl. In certain embodiments, at least one R^(b)is substituted aryl. In certain embodiments, at least one R^(b) isunsubstituted aryl. In certain embodiments, at least one R^(b) issubstituted phenyl. In certain embodiments, at least one R^(b) isunsubstituted phenyl. In certain embodiments, at least one R^(b) issubstituted heteroaryl. In certain embodiments, at least one R^(b) isunsubstituted heteroaryl. In certain embodiments, at least one R^(b) issubstituted pyridyl. In certain embodiments, at least one R^(b) isunsubstituted pyridyl.

Shown in FIG. 2 is a proposed mechanism for the intermolecular C—Hamination reaction of an azide RN₃ (e.g., AdN₃) and a C—H source R′CH₃(e.g., PhMe), catalyzed by a Fe^(II)Cl(L)-dipyrromethene complex (e.g.,3A), to yield an acyclic secondary amine RNHR′ (e.g., AdNHCH₂Ph). First,the Fe^(II)Cl(L)-dipyrromethene complex undergoes a ligand exchange toform Fe^(II)Cl(N₃R) (e.g., Fe^(II)Cl(N₃Ad))-dipyrromethene complex. TheFe^(II)Cl(N₃R)-dipyrromethene complex reacts with the C—H source R′CH₃(e.g., PhMe) to release a molecule of N₂ and form Fe^(III)Cl(.NR) (e.g.,Fe^(III)Cl(.NAd))-dipyrromethene complex (a “Fe^(III)(imido) complex”).Hydrogen transfer from R′CH₃ to the Fe^(III)(imido) complex gives riseto Fe^(III)Cl(NHR) (e.g., Fe^(III)Cl(NHAd))-dipyrromethene complex andR′CH₂. radical. A radical recombination furnishes the C—H aminationproduct RNHR′ (e.g., AdNHCH₂Ph), regenerates theFe^(II)Cl(L)-dipyrromethene complex, and therefore, completes thecatalytic cycle. The net effect of such a reaction is that a nitrenegroup RN: (e.g., AdN:) is transferred to a C—H source R′CH₃ (e.g.,PhMe). The mechanism for a similar reaction using compound 3B as thecatalyst instead of 3A is similar to or the same as the mechanismdescribed herein.

The steps of the methods of the invention may be performed under anysuitable conditions. A suitable condition is a combination of physicaland chemical parameters under which an intended product (e.g., anacyclic or cyclic amine) or intermediate may be formed using theinventive methods. A suitable condition may include a suitable solvent,such as an organic solvent (e.g., benzene, toluene, xylene, acetone,acetonitrile (ACN), N,N-dimethylformamide (DMF), N,N-dimethylacetamide(DMA), dimethysulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP),2-pyrrolidone, tetrahydrofuran (THF), or a mixture thereof). In certainembodiments, the suitable solvent is benzene.

A suitable condition may also include a suitable temperature under whichone or more steps of a method of the invention are performed. In certainembodiments, the suitable temperature is at least about 0° C., at leastabout 20° C., at least about 23° C., at least about 25° C., at leastabout 40° C., at least about 60° C., at least about 65° C., at leastabout 80° C., at least about 100° C., or at least about 120° C. Incertain embodiments, the suitable temperature is lower than about 120°C., lower than about 100° C., lower than about 80° C., lower than about65° C., lower than about 60° C., lower than about 40° C., lower thanabout 25° C., lower than about 23° C., lower than about 20° C., or lowerthan about 0° C. Combinations of the above-referenced ranges are alsopossible (e.g., a suitable temperature of at least about 0° C. and lowerthan about 65° C.). Other ranges are also possible. In certainembodiments, the suitable temperature is about 0° C. In certainembodiments, the suitable temperature is about 23° C. In certainembodiments, the suitable temperature is about 60° C. In certainembodiments, the suitable temperature is about 65° C. A suitabletemperature may be a variable temperature during one or more steps of amethod of the invention.

A suitable condition may also include a suitable pressure under whichone or more steps of the inventive methods are performed. In certainembodiments, the suitable pressure is about 1 atmosphere. A suitablepressure may also be higher or lower than 1 atmosphere.

A suitable condition may also include a suitable atmosphere under whichone or more steps of the inventive methods are performed. In certainembodiments, the suitable atmosphere is air. In certain embodiments, thesuitable atmosphere is an inert atmosphere. In certain embodiments, thesuitable atmosphere is a nitrogen or argon atmosphere.

A suitable condition may also include a suitable time duration that oneor more steps of a method of the invention last. In certain embodiments,the suitable time duration is in the order of minutes, hours (e.g.,about 6 or about 12 hours), or days (e.g., about 1 day).

A suitable condition may also include irradiation with microwave,shielding from ambient light, and/or agitating (e.g., stirring). One ormore intermediates resulting from a step of a method of the inventionmay be isolated and/or purified, and the isolated and/or purifiedintermediates may be reacted in a next step of the method. The isolatedand/or purified intermediates may be substantially pure or may containone or more other components, such as reagents and solvents employed inthe step yielding the intermediates and byproducts. The one or moreintermediates may also be reacted in a next step without being isolatedand/or purified.

Synthesis of Coordination Complexes of Cyclic Secondary Amines and aFerrous Compound

The present invention also provides methods of preparing compounds ofFormula (II-1), which are coordination complexes of cyclic secondaryamines and a ferrous compound:

and salts and stereoisomers thereof, the method comprising the steps of:

reacting an azide of Formula (F), or a salt or stereoisomer thereof,with a ferrous compound of Formula (G), or a salt or stereoisomerthereof:

wherein:

W is selected from the group consisting of mesityl and2,6-dichlorophenyl;

each occurrence of X is independently selected from the group consistingof —O—, —S—, —NR^(c)—, and —C(R^(d))₂—;

R^(c) is selected from the group consisting of hydrogen, a nitrogenprotecting group, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

each one of R⁷, R⁸, R⁹, and R¹⁰, and each occurrence of R^(d), areindependently selected from the group consisting of hydrogen, halogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(e),—N(R^(e))₂, —SR^(e), —CN, —C(═NR^(e))R^(e), —C(═NR^(e))OR^(e),—C(═NR^(e))N(R^(e))₂, —NO₂, —NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e),—NR^(e)C(═O)N(R^(e))₂, —C(═O)R^(e), —OC(═O)OR^(e), —OC(═O)N(R^(e))₂, and—ON(R^(e))₂;

each occurrence of R^(e) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, and a sulfur protecting group when attached to a sulfur atom, oroptionally two R^(e) groups are joined to form an optionally substitutedheterocyclic ring;

optionally two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joined toform an optionally substituted carbocyclyl or optionally substitutedheterocyclic ring;

Y is selected from the group consisting of N(R^(f))₃, R^(f)—O—R^(f),R^(f)—S—R^(f), optionally substituted heterocyclyl, and optionallysubstituted heteroaryl;

each occurrence of R^(f) is independently selected from the groupconsisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, and optionally substituted heteroaryl; and

n is 1, 2, 3, 4, or 5.

In compounds described herein, W is selected from the group consistingof mesityl and 2,6-dichlorophenyl. In certain embodiments, W is mesityl.In certain embodiments, W is 2,6-dichlorophenyl.

In compounds of Formulae (II-1) and (F), each occurrence of X isindependently selected from the group consisting of —O—, —S—, —NR^(c)—,and —C(R^(d))₂—. In certain embodiments, at least one X is —O—. Incertain embodiments, at least one X is —S—. In certain embodiments, atleast one X is —NR^(c)—. In certain embodiments, at least one X is—N(C₁₋₆ alkyl)-. In certain embodiments, at least one X is —N(Me)-. Incertain embodiments, at least one X is —NH—. In certain embodiments, atleast one X is —C(R^(d))₂—. In certain embodiments, at least one X is—C(C₁₋₆ alkyl)₂-. In certain embodiments, at least one X is —C(Me)₂-. Incertain embodiments, at least one X is —C(Et)₂-. In certain embodiments,at least one X is —C(Pr)₂—. In certain embodiments, at least one X is—C(Bu)₂-. In certain embodiments, at least one X is —C(C₁₋₆ alkenyl)₂-.In certain embodiments, at least one X is —C(vinyl)₂-. In certainembodiments, at least one X is —C(allyl)₂-. In certain embodiments, atleast one X is —CH(4-butenyl)-. In certain embodiments, at least one Xis —C(C₁₋₆ alkynyl)₂-. In certain embodiments, at least one X is—C(ethynyl)₂-. In certain embodiments, at least one X is —CH(R^(d))—. Incertain embodiments, at least one X is —CH(C₁₋₆ alkyl)-. In certainembodiments, at least one X is —CH(Me)-. In certain embodiments, atleast one X is —CH(Et)-. In certain embodiments, at least one X is—C(Pr)₂—. In certain embodiments, at least one X is —C(Bu)₂-. In certainembodiments, at least one X is —CH(C₁₋₆ alkenyl)-. In certainembodiments, at least one X is —CH(vinyl)-. In certain embodiments, atleast one X is —CH(allyl)-. In certain embodiments, at least one X is—CH(4-butenyl)-. In certain embodiments, at least one X is —CH(C₁₋₆alkynyl)-. In certain embodiments, at least one X is —CH(ethynyl)-. Incertain embodiments, at least one X is —CH(aryl)-. In certainembodiments, at least one X is —CH(Ph)-. In certain embodiments, atleast one X is —CH(heteroaryl)-. In certain embodiments, at least one Xis —CH(pyridyl)-. In certain embodiments, at least one X is—CH(OR^(e))—. In certain embodiments, at least one X is —CH(O-aryl)-. Incertain embodiments, at least one X is —CH(OPh)-. In certainembodiments, at least one X is —CH(O—C₁₋₆ alkyl)-. In certainembodiments, at least one X is —CH(OH)—. In certain embodiments, atleast one X is —CH(N(R^(e))₂)—. In certain embodiments, at least one Xis —CH(N(C₁₋₆ alkyl)₂)-. In certain embodiments, at least one X is—CH(NH₂)—. In certain embodiments, at least one X is —CH(C(═O)OR^(e))—.In certain embodiments, at least one X is —CH(C(═O)OMe)-. In certainembodiments, at least one X is —CH(C(═O)OEt)-. In certain embodiments,at least one X is —CH₂—.

In compounds of Formulae (II-1) and (F), when X is —NR^(c)—, R^(c) is asubstituent on the nitrogen atom. In certain embodiments, at least oneR^(c) is H. In certain embodiments, at least one R^(c) is substitutedalkyl. In certain embodiments, at least one R^(c) is unsubstitutedalkyl. In certain embodiments, at least one R^(c) is C₁₋₆ alkyl. Incertain embodiments, at least one R^(c) is methyl. In certainembodiments, at least one R^(c) is ethyl. In certain embodiments, atleast one R^(c) is propyl. In certain embodiments, at least one R^(c) isbutyl. In certain embodiments, at least one R^(c) is t-butyl. In certainembodiments, at least one R^(c) is Ad. In certain embodiments, at leastone R^(c) is substituted alkenyl. In certain embodiments, at least oneR^(c) is unsubstituted alkenyl. In certain embodiments, at least oneR^(c) is vinyl. In certain embodiments, at least one R^(c) issubstituted alkynyl. In certain embodiments, at least one R^(c) isunsubstituted alkynyl. In certain embodiments, at least one R^(c) isethynyl. In certain embodiments, at least one R^(c) is substitutedcarbocyclyl. In certain embodiments, at least one R^(c) is unsubstitutedcarbocyclyl. In certain embodiments, at least one R^(c) is cyclopropyl.In certain embodiments, at least one R^(c) is cyclobutyl. In certainembodiments, at least one R^(c) is cyclopentyl. In certain embodiments,at least one R^(c) is cyclohexyl. In certain embodiments, at least oneR^(c) is cycloheptyl. In certain embodiments, at least one R^(c) issubstituted heterocyclyl. In certain embodiments, at least one R^(c) isunsubstituted heterocyclyl. In certain embodiments, at least one R^(c)is substituted aryl. In certain embodiments, at least one R^(c) isunsubstituted aryl. In certain embodiments, at least one R^(c) issubstituted phenyl. In certain embodiments, at least one R^(c) is tolyl.In certain embodiments, at least one R^(c) is 4-tolyl. In certainembodiments, at least one R^(c) is Mes. In certain embodiments, at leastone R^(c) is unsubstituted phenyl. In certain embodiments, at least oneR^(c) is substituted naphthyl. In certain embodiments, at least oneR^(c) is unsubstituted naphthyl. In certain embodiments, at least oneR^(c) is substituted heteroaryl. In certain embodiments, at least oneR^(c) is unsubstituted heteroaryl. In certain embodiments, at least oneR^(c) is monocyclic heteroaryl. In certain embodiments, at least oneR^(c) is 5-membered monocyclic heteroaryl. In certain embodiments, atleast one R^(c) is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one R^(c) is 5-membered monocyclic heteroaryl, wherein only two ofthe five atoms in the ring of the heteroaryl are independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, at least one R^(c) is 5-membered monocyclic heteroaryl,wherein only three of the five atoms in the ring of the heteroaryl areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, at least one R^(c) is tetrazolyl. Incertain embodiments, at least one R^(c) is 6-membered monocyclicheteroaryl. In certain embodiments, at least one R^(c) is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, at least one R^(c) is6-membered monocyclic heteroaryl, wherein only two of the six atoms inthe ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one R^(c) is triazinyl. In certain embodiments, at least one R^(c)is tetrazinyl. In certain embodiments, at least one R^(c) is bicyclicheteroaryl, wherein the point of attachment may be at any atom of theheteroaryl, as valency permits. In certain embodiments, at least oneR^(c) is a monocyclic heteroaryl fused with phenyl. In certainembodiments, at least one R^(c) is a 5-membered monocyclic heteroarylfused with phenyl. In certain embodiments, at least one R^(c) is a6-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, at least one R^(c) is a monocyclic heteroaryl fused withanother monocyclic heteroaryl. In certain embodiments, at least oneR^(c) is a 5-membered monocyclic heteroaryl fused with another5-membered monocyclic heteroaryl. In certain embodiments, at least oneR^(c) is a 5-membered monocyclic heteroaryl fused with a 6-memberedmonocyclic heteroaryl. In certain embodiments, at least one R^(c) is a6-membered monocyclic heteroaryl fused with another 6-memberedmonocyclic heteroaryl. In certain embodiments, at least one R^(c) is anitrogen protecting group. In certain embodiments, at least one R^(c) isBn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

In compounds of Formulae (II-1) and (F), when X is —C(R^(d))₂—, at leastone R^(d) is a substituent on the carbon atom. In certain embodiments,at least one R^(d) is H. In certain embodiments, at least one R^(d) ishalogen. In certain embodiments, at least one R^(d) is F. In certainembodiments, at least one R^(d) is Cl. In certain embodiments, at leastone R^(d) is Br. In certain embodiments, at least one R^(d) is I(iodine). In certain embodiments, at least one R^(d) is substitutedacyl. In certain embodiments, at least one R^(d) is unsubstituted acyl.In certain embodiments, at least one R^(d) is —C(═O)R^(e). In certainembodiments, at least one R^(d) is acetyl. In certain embodiments, atleast one R^(d) is —C(═O)OR^(e). In certain embodiments, at least oneR^(d) is —C(═O)N(R^(e))₂. In certain embodiments, at least one R^(d) issubstituted alkyl. In certain embodiments, at least one R^(d) isunsubstituted alkyl. In certain embodiments, at least one R^(d) is C₁₋₆alkyl. In certain embodiments, at least one R^(d) is methyl. In certainembodiments, at least one R^(d) is ethyl. In certain embodiments, atleast one R^(d) is propyl. In certain embodiments, at least one R^(d) isbutyl. In certain embodiments, at least one R^(d) is Ad. In certainembodiments, at least one R^(d) is substituted alkenyl. In certainembodiments, at least one R^(d) is unsubstituted alkenyl. In certainembodiments, at least one R^(d) is vinyl. In certain embodiments, atleast one R^(d) is substituted alkynyl. In certain embodiments, at leastone R^(d) is unsubstituted alkynyl. In certain embodiments, at least oneR^(d) is ethynyl. In certain embodiments, at least one R^(d) issubstituted carbocyclyl. In certain embodiments, at least one R^(d) isunsubstituted carbocyclyl. In certain embodiments, at least one R^(d) iscyclopropyl. In certain embodiments, at least one R^(d) is cyclobutyl.In certain embodiments, at least one R^(d) is cyclopentyl. In certainembodiments, at least one R^(d) is cyclohexyl. In certain embodiments,at least one R^(d) is cycloheptyl. In certain embodiments, at least oneR^(d) is substituted heterocyclyl. In certain embodiments, at least oneR^(d) is unsubstituted heterocyclyl. In certain embodiments, at leastone R^(d) is substituted aryl. In certain embodiments, at least oneR^(d) is unsubstituted aryl. In certain embodiments, at least one R^(d)is substituted phenyl. In certain embodiments, at least one R^(d) isunsubstituted phenyl. In certain embodiments, at least one R^(d) issubstituted naphthyl. In certain embodiments, at least one R^(d) isunsubstituted naphthyl. In certain embodiments, at least one R^(d) issubstituted heteroaryl. In certain embodiments, at least one R^(d) isunsubstituted heteroaryl. In certain embodiments, at least one R^(d) ismonocyclic heteroaryl. In certain embodiments, at least one R^(d) is5-membered monocyclic heteroaryl. In certain embodiments, at least oneR^(d) is 5-membered monocyclic heteroaryl, wherein only one of the fiveatoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one R^(d) is 5-membered monocyclic heteroaryl, wherein only two ofthe five atoms in the ring of the heteroaryl are independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, at least one R^(d) is 5-membered monocyclic heteroaryl,wherein only three of the five atoms in the ring of the heteroaryl areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, at least one R^(d) is tetrazolyl. Incertain embodiments, at least one R^(d) is 6-membered monocyclicheteroaryl. In certain embodiments, at least one R^(d) is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, at least one R^(d) is6-membered monocyclic heteroaryl, wherein only two of the six atoms inthe ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one R^(d) is triazinyl. In certain embodiments, at least one R^(d)is tetrazinyl. In certain embodiments, at least one R^(d) is bicyclicheteroaryl, wherein the point of attachment may be at any atom of theheteroaryl, as valency permits. In certain embodiments, at least oneR^(d) is a monocyclic heteroaryl fused with phenyl. In certainembodiments, at least one R^(d) is a 5-membered monocyclic heteroarylfused with phenyl. In certain embodiments, at least one R^(d) is a6-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, at least one R^(d) is a monocyclic heteroaryl fused withanother monocyclic heteroaryl. In certain embodiments, at least oneR^(d) is a 5-membered monocyclic heteroaryl fused with another5-membered monocyclic heteroaryl. In certain embodiments, at least oneR^(d) is a 5-membered monocyclic heteroaryl fused with a 6-memberedmonocyclic heteroaryl. In certain embodiments, at least one R^(d) is a6-membered monocyclic heteroaryl fused with another 6-memberedmonocyclic heteroaryl. In certain embodiments, at least one R^(d) is—OR^(e). In certain embodiments, at least one R^(d) is —OH when attachedto an sp³ carbon atom. In certain embodiments, at least one R^(d) is—SR^(e). In certain embodiments, at least one R^(d) is —SH when attachedto an sp³ carbon atom. In certain embodiments, at least one R^(d) is—N(R^(e))₂. In certain embodiments, at least one R^(d) is —NH₂ whenattached to an sp³ carbon atom. In certain embodiments, at least oneR^(d) is —CN. In certain embodiments, at least one R^(d) is —SCN. Incertain embodiments, at least one R^(d) is —C(═NR^(e))R^(e),—C(═NR^(e))OR^(e), or —C(═NR^(e))N(R^(e))₂. In certain embodiments, atleast one R^(d) is —C(═O)R^(e), —C(═O)OR^(e), or —C(═O)N(R^(e))₂. Incertain embodiments, at least one R^(d) is —NO₂. In certain embodiments,at least one R^(d) is —NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e), or—NR^(e)C(═O)N(R^(e))₂. In certain embodiments, at least one R^(d) is—OC(═O)R^(e), —OC(═O)OR^(e), or —OC(═O)N(R^(e))₂. In certainembodiments, at least one R^(d) is —ON(R^(e))₂.

In certain embodiments, n is 1. In certain embodiments, n is 2. Incertain embodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5.

Compounds of Formulae (II-1) and (F) include a substituent R⁷. Incertain embodiments, R⁷ is H. In certain embodiments, R⁷ is halogen. Incertain embodiments, R⁷ is F. In certain embodiments, R⁷ is Cl. Incertain embodiments, R⁷ is Br. In certain embodiments, R⁷ is I (iodine).In certain embodiments, R⁷ is substituted acyl. In certain embodiments,R⁷ is unsubstituted acyl. In certain embodiments, R⁷ is —C(═O)R^(e). Incertain embodiments, R⁷ is acetyl. In certain embodiments, R⁷ is—C(═O)OR^(e). In certain embodiments, R⁷ is —C(═O)N(R^(e))₂. In certainembodiments, R⁷ is substituted alkyl. In certain embodiments, R⁷ isunsubstituted alkyl. In certain embodiments, R⁷ is C₁₋₆ alkyl. Incertain embodiments, R⁷ is methyl. In certain embodiments, R⁷ is ethyl.In certain embodiments, R⁷ is propyl. In certain embodiments, R⁷ isbutyl. In certain embodiments, R⁷ is Ad. In certain embodiments, R⁷ issubstituted alkenyl. In certain embodiments, R⁷ is unsubstitutedalkenyl. In certain embodiments, R⁷ is vinyl. In certain embodiments, R⁷is substituted alkynyl. In certain embodiments, R⁷ is unsubstitutedalkynyl. In certain embodiments, R⁷ is ethynyl. In certain embodiments,R⁷ is substituted carbocyclyl. In certain embodiments, R⁷ isunsubstituted carbocyclyl. In certain embodiments, R⁷ is cyclopropyl. Incertain embodiments, R⁷ is cyclobutyl. In certain embodiments, R⁷ iscyclopentyl. In certain embodiments, R⁷ is cyclohexyl. In certainembodiments, R⁷ is cycloheptyl. In certain embodiments, R⁷ issubstituted heterocyclyl. In certain embodiments, R⁷ is unsubstitutedheterocyclyl. In certain embodiments, R⁷ is substituted aryl. In certainembodiments, R⁷ is unsubstituted aryl. In certain embodiments, R⁷ issubstituted phenyl. In certain embodiments, R⁷ is unsubstituted phenyl.In certain embodiments, R⁷ is substituted naphthyl. In certainembodiments, R⁷ is unsubstituted naphthyl. In certain embodiments, R⁷ issubstituted heteroaryl. In certain embodiments, R⁷ is unsubstitutedheteroaryl. In certain embodiments, R⁷ is monocyclic heteroaryl. Incertain embodiments, R⁷ is 5-membered monocyclic heteroaryl. In certainembodiments, R⁷ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁷is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁷is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R⁷ is tetrazolyl. In certain embodiments, R⁷ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R⁷ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R⁷ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R⁷ is triazinyl.In certain embodiments, R⁷ is tetrazinyl. In certain embodiments, R⁷ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R⁷ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R⁷ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R⁷ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R⁷ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R⁷ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R⁷ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R⁷ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R⁷ is —OR^(e).In certain embodiments, R⁷ is —OH when attached to an sp³ carbon atom.In certain embodiments, R⁷ is —SR^(e). In certain embodiments, R⁷ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R⁷ is—N(R^(e))₂. In certain embodiments, R⁷ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R⁷ is —CN. In certain embodiments,R⁷ is —SCN. In certain embodiments, R⁷ is —C(═NR^(e))R^(e),—C(═NR^(e))OR^(e), or —C(═NR^(e))N(R^(e))₂. In certain embodiments, R⁷is —C(═O)R^(e), —C(═O)OR^(e), or —C(═O)N(R^(e))₂. In certainembodiments, R⁷ is —NO₂. In certain embodiments, R⁷ is—NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e), or —NR^(e)C(═O)N(R^(e))₂. Incertain embodiments, R⁷ is —OC(═O)R^(e), —OC(═O)OR^(e), or—OC(═O)N(R^(e))₂. In certain embodiments, R⁷ is —ON(R^(e))₂.

Compounds of Formulae (II-1) and (F) also include a substituent R⁸. Incertain embodiments, R⁸ is H. In certain embodiments, R⁸ is halogen. Incertain embodiments, R⁸ is F. In certain embodiments, R⁸ is Cl. Incertain embodiments, R⁸ is Br. In certain embodiments, R⁸ is I (iodine).In certain embodiments, R⁸ is substituted acyl. In certain embodiments,R⁸ is unsubstituted acyl. In certain embodiments, R⁸ is —C(═O)R^(e). Incertain embodiments, R⁸ is acetyl. In certain embodiments, R⁸ is—C(═O)OR^(e). In certain embodiments, R⁸ is —C(═O)N(R^(e))₂. In certainembodiments, R⁸ is substituted alkyl. In certain embodiments, R⁸ isunsubstituted alkyl. In certain embodiments, R⁸ is C₁₋₆ alkyl. Incertain embodiments, R⁸ is methyl. In certain embodiments, R⁸ is ethyl.In certain embodiments, R⁸ is propyl. In certain embodiments, R⁸ isbutyl. In certain embodiments, R⁸ is Ad. In certain embodiments, R⁸ issubstituted alkenyl. In certain embodiments, R⁸ is unsubstitutedalkenyl. In certain embodiments, R⁸ is vinyl. In certain embodiments, R⁸is substituted alkynyl. In certain embodiments, R⁸ is unsubstitutedalkynyl. In certain embodiments, R⁸ is ethynyl. In certain embodiments,R⁸ is substituted carbocyclyl. In certain embodiments, R⁸ isunsubstituted carbocyclyl. In certain embodiments, R⁸ is cyclopropyl. Incertain embodiments, R⁸ is cyclobutyl. In certain embodiments, R⁸ iscyclopentyl. In certain embodiments, R⁸ is cyclohexyl. In certainembodiments, R⁸ is cycloheptyl. In certain embodiments, R⁸ issubstituted heterocyclyl. In certain embodiments, R⁸ is unsubstitutedheterocyclyl. In certain embodiments, R⁸ is substituted aryl. In certainembodiments, R⁸ is unsubstituted aryl. In certain embodiments, R⁸ issubstituted phenyl. In certain embodiments, R⁸ is unsubstituted phenyl.In certain embodiments, R⁸ is substituted naphthyl. In certainembodiments, R⁸ is unsubstituted naphthyl. In certain embodiments, R⁸ issubstituted heteroaryl. In certain embodiments, R⁸ is unsubstitutedheteroaryl. In certain embodiments, R⁸ is monocyclic heteroaryl. Incertain embodiments, R⁸ is 5-membered monocyclic heteroaryl. In certainembodiments, R⁸ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁸is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁸is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R⁸ is tetrazolyl. In certain embodiments, R⁸ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R⁸ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R⁸ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R⁸ is triazinyl.In certain embodiments, R⁸ is tetrazinyl. In certain embodiments, R⁸ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R⁸ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R⁸ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R⁸ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R⁸ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R⁸ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R⁸ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R⁸ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R⁸ is —OR^(e).In certain embodiments, R⁸ is —OH when attached to an sp³ carbon atom.In certain embodiments, R⁸ is —SR^(e). In certain embodiments, R⁸ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R⁸ is—N(R^(e))₂. In certain embodiments, R⁸ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R⁸ is —CN. In certain embodiments,R⁸ is —SCN. In certain embodiments, R⁸ is —C(═NR^(e))R^(e),—C(═NR^(e))OR^(e), or —C(═NR^(e))N(R^(e))₂. In certain embodiments, R⁸is —C(═O)R^(e), —C(═O)OR^(e), or —C(═O)N(R^(e))₂. In certainembodiments, R⁸ is —NO₂. In certain embodiments, R⁸ is—NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e), or —NR^(e)C(═O)N(R^(e))₂. Incertain embodiments, R⁸ is —OC(═O)R^(e), —OC(═O)OR^(e), or—OC(═O)N(R^(e))₂. In certain embodiments, R⁸ is —ON(R^(e))₂.

Compounds of Formulae (II-1) and (F) further include a substituent R⁹.In certain embodiments, R⁹ is H. In certain embodiments, R⁹ is halogen.In certain embodiments, R⁹ is F. In certain embodiments, R⁹ is Cl. Incertain embodiments, R⁹ is Br. In certain embodiments, R⁹ is I (iodine).In certain embodiments, R⁹ is substituted acyl. In certain embodiments,R⁹ is unsubstituted acyl. In certain embodiments, R⁹ is —C(═O)R^(e). Incertain embodiments, R⁹ is acetyl. In certain embodiments, R⁹ is—C(═O)OR^(e). In certain embodiments, R⁹ is —C(═O)N(R^(e))₂. In certainembodiments, R⁹ is substituted alkyl. In certain embodiments, R⁹ isunsubstituted alkyl. In certain embodiments, R⁹ is C₁₋₆ alkyl. Incertain embodiments, R⁹ is methyl. In certain embodiments, R⁹ is ethyl.In certain embodiments, R⁹ is propyl. In certain embodiments, R⁹ isbutyl. In certain embodiments, R⁹ is Ad. In certain embodiments, R⁹ issubstituted alkenyl. In certain embodiments, R⁹ is unsubstitutedalkenyl. In certain embodiments, R⁹ is vinyl. In certain embodiments, R⁹is substituted alkynyl. In certain embodiments, R⁹ is unsubstitutedalkynyl. In certain embodiments, R⁹ is ethynyl. In certain embodiments,R⁹ is substituted carbocyclyl. In certain embodiments, R⁹ isunsubstituted carbocyclyl. In certain embodiments, R⁹ is cyclopropyl. Incertain embodiments, R⁹ is cyclobutyl. In certain embodiments, R⁹ iscyclopentyl. In certain embodiments, R⁹ is cyclohexyl. In certainembodiments, R⁹ is cycloheptyl. In certain embodiments, R⁹ issubstituted heterocyclyl. In certain embodiments, R⁹ is unsubstitutedheterocyclyl. In certain embodiments, R⁹ is substituted aryl. In certainembodiments, R⁹ is unsubstituted aryl. In certain embodiments, R⁹ issubstituted phenyl. In certain embodiments, R⁹ is unsubstituted phenyl.In certain embodiments, R⁹ is substituted naphthyl. In certainembodiments, R⁹ is unsubstituted naphthyl. In certain embodiments, R⁹ issubstituted heteroaryl. In certain embodiments, R⁹ is unsubstitutedheteroaryl. In certain embodiments, R⁹ is monocyclic heteroaryl. Incertain embodiments, R⁹ is 5-membered monocyclic heteroaryl. In certainembodiments, R⁹ is 5-membered monocyclic heteroaryl, wherein only one ofthe five atoms in the ring of the heteroaryl is selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁹is 5-membered monocyclic heteroaryl, wherein only two of the five atomsin the ring of the heteroaryl are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, R⁹is 5-membered monocyclic heteroaryl, wherein only three of the fiveatoms in the ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, R⁹ is tetrazolyl. In certain embodiments, R⁹ is 6-memberedmonocyclic heteroaryl. In certain embodiments, R⁹ is 6-memberedmonocyclic heteroaryl, wherein only one of the six atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R⁹ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R⁹ is triazinyl.In certain embodiments, R⁹ is tetrazinyl. In certain embodiments, R⁹ isbicyclic heteroaryl, wherein the point of attachment may be at any atomof the heteroaryl, as valency permits. In certain embodiments, R⁹ is amonocyclic heteroaryl fused with phenyl. In certain embodiments, R⁹ is a5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R⁹ is a 6-membered monocyclic heteroaryl fused with phenyl.In certain embodiments, R⁹ is a monocyclic heteroaryl fused with anothermonocyclic heteroaryl. In certain embodiments, R⁹ is a 5-memberedmonocyclic heteroaryl fused with another 5-membered monocyclicheteroaryl. In certain embodiments, R⁹ is a 5-membered monocyclicheteroaryl fused with a 6-membered monocyclic heteroaryl. In certainembodiments, R⁹ is a 6-membered monocyclic heteroaryl fused with another6-membered monocyclic heteroaryl. In certain embodiments, R⁹ is —OR^(e).In certain embodiments, R⁹ is —OH when attached to an sp³ carbon atom.In certain embodiments, R⁹ is —SR^(e). In certain embodiments, R⁹ is —SHwhen attached to an sp³ carbon atom. In certain embodiments, R⁹ is—N(R^(e))₂. In certain embodiments, R⁹ is —NH₂ when attached to an sp³carbon atom. In certain embodiments, R⁹ is —CN. In certain embodiments,R⁹ is —SCN. In certain embodiments, R⁹ is —C(═NR^(e))R^(e),—C(═NR^(e))OR^(e), or —C(═NR^(e))N(R^(e))₂. In certain embodiments, R⁹is —C(═O)R^(e), —C(═O)OR^(e), or —C(═O)N(R^(e))₂. In certainembodiments, R⁹ is —NO₂. In certain embodiments, R⁹ is—NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e), or —NR^(e)C(═O)N(R^(e))₂. Incertain embodiments, R⁹ is —OC(═O)R^(e), —OC(═O)OR^(e), or—OC(═O)N(R^(e))₂. In certain embodiments, R⁹ is —ON(R^(e))₂.

Compounds of Formulae (II-1) and (F) still include a substituent R¹⁰. Incertain embodiments, R¹⁰ is H. In certain embodiments, R¹⁰ is halogen.In certain embodiments, R¹⁰ is F. In certain embodiments, R¹⁰ is Cl. Incertain embodiments, R¹⁰ is Br. In certain embodiments, R¹⁰ is I(iodine). In certain embodiments, R¹⁰ is substituted acyl. In certainembodiments, R¹⁰ is unsubstituted acyl. In certain embodiments, R¹⁰ is—C(═O)R^(e). In certain embodiments, R¹⁰ is acetyl. In certainembodiments, R¹⁰ is —C(═O)OR^(e). In certain embodiments, R¹⁰ is—C(═O)N(R^(e))₂. In certain embodiments, R¹⁰ is substituted alkyl. Incertain embodiments, R¹⁰ is unsubstituted alkyl. In certain embodiments,R¹⁰ is C₁₋₆ alkyl. In certain embodiments, R¹⁰ is methyl. In certainembodiments, R¹⁰ is ethyl. In certain embodiments, R¹⁰ is propyl. Incertain embodiments, R¹⁰ is butyl. In certain embodiments, R¹⁰ is Ad. Incertain embodiments, R¹⁰ is substituted alkenyl. In certain embodiments,R¹⁰ is unsubstituted alkenyl. In certain embodiments, R¹⁰ is vinyl. Incertain embodiments, R¹⁰ is substituted alkynyl. In certain embodiments,R¹⁰ is unsubstituted alkynyl. In certain embodiments, R¹⁰ is ethynyl. Incertain embodiments, R¹⁰ is substituted carbocyclyl. In certainembodiments, R¹⁰ is unsubstituted carbocyclyl. In certain embodiments,R¹⁰ is cyclopropyl. In certain embodiments, R¹⁰ is cyclobutyl. Incertain embodiments, R¹⁰ is cyclopentyl. In certain embodiments, R¹⁰ iscyclohexyl. In certain embodiments, R¹⁰ is cycloheptyl. In certainembodiments, R¹⁰ is substituted heterocyclyl. In certain embodiments,R¹⁰ is unsubstituted heterocyclyl. In certain embodiments, R¹⁰ issubstituted aryl. In certain embodiments, R¹⁰ is unsubstituted aryl. Incertain embodiments, R¹⁰ is substituted phenyl. In certain embodiments,R¹⁰ is unsubstituted phenyl. In certain embodiments, R¹⁰ is substitutednaphthyl. In certain embodiments, R¹⁰ is unsubstituted naphthyl. Incertain embodiments, R¹⁰ is substituted heteroaryl. In certainembodiments, R¹⁰ is unsubstituted heteroaryl. In certain embodiments,R¹⁰ is monocyclic heteroaryl. In certain embodiments, R¹⁰ is 5-memberedmonocyclic heteroaryl. In certain embodiments, R¹⁰ is 5-memberedmonocyclic heteroaryl, wherein only one of the five atoms in the ring ofthe heteroaryl is selected from the group consisting of nitrogen,oxygen, and sulfur. In certain embodiments, R¹⁰ is 5-membered monocyclicheteroaryl, wherein only two of the five atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R¹⁰ is 5-memberedmonocyclic heteroaryl, wherein only three of the five atoms in the ringof the heteroaryl are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, R¹⁰ istetrazolyl. In certain embodiments, R¹⁰ is 6-membered monocyclicheteroaryl. In certain embodiments, R¹⁰ is 6-membered monocyclicheteroaryl, wherein only one of the six atoms in the ring of theheteroaryl is selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, R¹⁰ is 6-membered monocyclicheteroaryl, wherein only two of the six atoms in the ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, R¹⁰ is triazinyl.In certain embodiments, R¹⁰ is tetrazinyl. In certain embodiments, R¹⁰is bicyclic heteroaryl, wherein the point of attachment may be at anyatom of the heteroaryl, as valency permits. In certain embodiments, R¹⁰is a monocyclic heteroaryl fused with phenyl. In certain embodiments,R¹⁰ is a 5-membered monocyclic heteroaryl fused with phenyl. In certainembodiments, R¹⁰ is a 6-membered monocyclic heteroaryl fused withphenyl. In certain embodiments, R¹⁰ is a monocyclic heteroaryl fusedwith another monocyclic heteroaryl. In certain embodiments, R¹⁰ is a5-membered monocyclic heteroaryl fused with another 5-memberedmonocyclic heteroaryl. In certain embodiments, R¹⁰ is a 5-memberedmonocyclic heteroaryl fused with a 6-membered monocyclic heteroaryl. Incertain embodiments, R¹⁰ is a 6-membered monocyclic heteroaryl fusedwith another 6-membered monocyclic heteroaryl. In certain embodiments,R¹⁰ is —OR^(e). In certain embodiments, R¹⁰ is —OH when attached to ansp³ carbon atom. In certain embodiments, R¹⁰ is —SR^(e). In certainembodiments, R¹⁰ is —SH when attached to an sp³ carbon atom. In certainembodiments, R¹⁰ is —N(R^(e))₂. In certain embodiments, R¹⁰ is —NH₂ whenattached to an sp³ carbon atom. In certain embodiments, R¹⁰ is —CN. Incertain embodiments, R¹⁰ is —SCN. In certain embodiments, R¹⁰ is—C(═NR^(e))R^(e), —C(═NR^(e))OR^(e), or —C(═NR^(e))N(R^(e))₂. In certainembodiments, R¹⁰ is —C(═O)R^(e), —C(═O)OR^(e), or —C(═O)N(R^(e))₂. Incertain embodiments, R¹⁰ is —NO₂. In certain embodiments, R¹⁰ is—NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e), or —NR^(e)C(═O)N(R^(e)). Incertain embodiments, R¹⁰ is —OC(═O)R^(e), —OC(═O)OR^(e), or—OC(═O)N(R^(e))₂. In certain embodiments, R¹⁰ is —ON(R^(e))₂.

In certain embodiments, at least one R^(e) is H. In certain embodiments,at least one R^(e) is substituted acyl. In certain embodiments, at leastone R^(e) is unsubstituted acyl. In certain embodiments, at least oneR^(e) is acetyl. In certain embodiments, at least one R^(e) issubstituted alkyl. In certain embodiments, at least one R^(e) isunsubstituted alkyl. In certain embodiments, at least one R^(e) is C₁₋₆alkyl. In certain embodiments, at least one R^(e) is methyl. In certainembodiments, at least one R^(e) is ethyl. In certain embodiments, atleast one R^(e) is propyl. In certain embodiments, at least one R^(e) isbutyl. In certain embodiments, at least one R^(e) is substitutedalkenyl. In certain embodiments, at least one R^(e) is unsubstitutedalkenyl. In certain embodiments, at least one R^(e) is vinyl. In certainembodiments, at least one R^(e) is substituted alkynyl. In certainembodiments, at least one R^(e) is unsubstituted alkynyl. In certainembodiments, at least one R^(e) is ethynyl. In certain embodiments, atleast one R^(e) is substituted carbocyclyl. In certain embodiments, atleast one R^(e) is unsubstituted carbocyclyl. In certain embodiments, atleast one R^(e) is cyclopropyl. In certain embodiments, at least oneR^(e) is cyclobutyl. In certain embodiments, at least one R^(e) iscyclopentyl. In certain embodiments, at least one R^(e) is cyclohexyl.In certain embodiments, at least one R^(e) is cycloheptyl. In certainembodiments, at least one R^(e) is substituted heterocyclyl. In certainembodiments, at least one R^(e) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(e) is substituted aryl. In certainembodiments, at least one R^(e) is unsubstituted aryl. In certainembodiments, at least one R^(e) is substituted phenyl. In certainembodiments, at least one R^(e) is unsubstituted phenyl. In certainembodiments, at least one R^(e) is substituted heteroaryl. In certainembodiments, at least one R^(e) is unsubstituted heteroaryl. In certainembodiments, at least one R^(e) is substituted pyridyl. In certainembodiments, at least one R^(e) is unsubstituted pyridyl. In certainembodiments, at least one R^(e) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, at least one R^(e)is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts whenattached to a nitrogen atom. In certain embodiments, at least one R^(e)is an oxygen protecting group when attached to an oxygen atom. Incertain embodiments, at least one R^(e) is silyl, TBDPS, TBDMS, TIPS,TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl whenattached to an oxygen atom. In certain embodiments, two R^(e) groups arejoined to form a substituted heterocyclic ring. In certain embodiments,two R^(e) groups are joined to form an unsubstituted heterocyclic ring.In certain embodiments, two R^(e) groups are joined to form asubstituted heteroaryl ring. In certain embodiments, two R^(e) groupsare joined to form an unsubstituted heteroaryl ring.

In compounds of Formulae (II-1) and (F), any two of R⁷, R⁸, R⁹, R¹⁰,R^(c), and R^(d) groups may be joined to form a optionally substitutedcarbocyclyl ring, or optionally substituted heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups arejoined to form a optionally substituted cyclopropyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cyclobutyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cyclopentyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cyclohexyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cycloheptyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cyclooctyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cyclononyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted cyclodecyl ring. In certainembodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joinedto form a optionally substituted 4-membered heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups arejoined to form a optionally substituted 5-membered heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups arejoined to form a optionally substituted 6-membered heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups arejoined to form a optionally substituted 7-membered heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(e), and R^(d) groups arejoined to form a optionally substituted 8-membered heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(e), and R^(d) groups arejoined to form a optionally substituted 9-membered heterocyclic ring. Incertain embodiments, two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups arejoined to form a optionally substituted 10-membered heterocyclic ring.In certain embodiments, R⁷ and R⁸ are joined to form a optionallysubstituted carbocyclyl ring. In certain embodiments, R⁷ and R⁸ arejoined to form a optionally substituted heterocyclic ring. In certainembodiments, R⁷ and R⁹ are joined to form a optionally substitutedcarbocyclyl ring. In certain embodiments, R⁷ and R⁹ are joined to form aoptionally substituted heterocyclic ring. In certain embodiments, R⁷ andR¹⁰ are joined to form a optionally substituted carbocyclyl ring. Incertain embodiments, R⁷ and R¹⁰ are joined to form a optionallysubstituted heterocyclic ring. In certain embodiments, R⁷ and R^(c) arejoined to form a optionally substituted carbocyclyl ring. In certainembodiments, R⁷ and R^(c) are joined to form a optionally substitutedheterocyclic ring. In certain embodiments, R⁷ and R^(d) are joined toform a optionally substituted carbocyclyl ring. In certain embodiments,R⁷ and R^(d) are joined to form a optionally substituted heterocyclicring. In certain embodiments, R⁸ and R⁹ are joined to form a optionallysubstituted carbocyclyl ring. In certain embodiments, R⁸ and R⁹ arejoined to form a optionally substituted heterocyclic ring. In certainembodiments, R⁸ and R¹⁰ are joined to form a optionally substitutedcarbocyclyl ring. In certain embodiments, R⁸ and R¹⁰ are joined to forma optionally substituted heterocyclic ring. In certain embodiments, R⁸and R^(c) are joined to form a optionally substituted carbocyclyl ring.In certain embodiments, R⁸ and R^(c) are joined to form a optionallysubstituted heterocyclic ring. In certain embodiments, R⁸ and R^(d) arejoined to form a optionally substituted carbocyclyl ring. In certainembodiments, R^(e) and R^(d) are joined to form a optionally substitutedheterocyclic ring. In certain embodiments, R⁹ and R¹⁰ are joined to forma optionally substituted carbocyclyl ring. In certain embodiments, R⁹and R¹⁰ are joined to form a optionally substituted heterocyclic ring.In certain embodiments, R⁹ and R^(c) are joined to form a optionallysubstituted carbocyclyl ring. In certain embodiments, R⁹ and R^(c) arejoined to form a optionally substituted heterocyclic ring. In certainembodiments, R⁹ and R^(d) are joined to form a optionally substitutedcarbocyclyl ring. In certain embodiments, R⁹ and R^(d) are joined toform a optionally substituted heterocyclic ring. In certain embodiments,R¹⁰ and R^(c) are joined to form a optionally substituted carbocyclylring. In certain embodiments, R¹⁰ and R^(c) are joined to form aoptionally substituted heterocyclic ring. In certain embodiments, R¹⁰and R^(d) are joined to form a optionally substituted carbocyclyl ring.In certain embodiments, R¹⁰ and R^(d) are joined to form a optionallysubstituted heterocyclic ring. In certain embodiments, R^(c) and R^(d)are joined to form a optionally substituted carbocyclyl ring. In certainembodiments, R^(c) and R^(d) are joined to form a optionally substitutedheterocyclic ring.

In certain embodiments, R⁷ and R⁸ are each independently selected fromthe group consisting of substituted alkyl, unsubstituted alkyl,substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, andunsubstituted alkynyl. In certain embodiments, R⁷ and R⁸ are eachindependently selected from the group consisting of substituted alkyland unsubstituted alkyl. In certain embodiments, R⁷ and R⁸ are each C₁₋₆alkyl. In certain embodiments, R⁷ and R⁸ are each methyl. In certainembodiments, R⁷ and R⁸ are each independently selected from the groupconsisting of methyl, ethyl, propyl, and butyl.

In certain embodiments, R⁷ is optionally substituted alkyl; and R⁸ isoptionally substituted aryl. In certain embodiments, R⁷ is optionallysubstituted alkyl; and R⁸ is optionally substituted phenyl. In certainembodiments, R⁷ is C₁₋₆ alkyl; and R⁸ is optionally substituted aryl. Incertain embodiments, R⁷ is C₁₋₆ alkyl; and R⁸ is optionally substitutedphenyl. In certain embodiments, R⁷ is methyl; and R⁸ is phenyl. Incertain embodiments, R⁸ is optionally substituted alkyl; and R⁷ isoptionally substituted aryl. In certain embodiments, R⁸ is optionallysubstituted alkyl; and R⁷ is optionally substituted phenyl. In certainembodiments, R⁸ is C₁₋₆ alkyl; and R⁷ is optionally substituted aryl. Incertain embodiments, R⁸ is C₁₋₆ alkyl; and R⁷ is optionally substitutedphenyl. In certain embodiments, R⁸ is methyl; and R⁷ is phenyl.

In certain embodiments, R⁷ is H; and R⁸ is substituted alkyl. In certainembodiments, R⁷ is H; and R⁸ is unsubstituted alkyl. In certainembodiments, R⁷ is H; and R⁸ is C₁₋₆ alkyl. In certain embodiments, R⁷is H; and R⁸ is methyl. In certain embodiments, R⁷ is H; and R⁸ isethyl. In certain embodiments, R⁷ is H; and R⁸ is propyl. In certainembodiments, R⁷ is H; and R⁸ is butyl. In certain embodiments, R⁷ is H;and R⁸ is substituted alkenyl. In certain embodiments, R⁷ is H; and R⁸is unsubstituted alkenyl. In certain embodiments, R⁷ is H; and R⁸ isC₁₋₆ alkenyl. In certain embodiments, R⁷ is H; and R⁸ is vinyl. Incertain embodiments, R⁷ is H; and R⁸ is allyl. In certain embodiments,R⁷ is H; and R⁸ is 4-butenyl. In certain embodiments, R⁷ is H; and R⁸ issubstituted alkynyl. In certain embodiments, R⁷ is H; and R⁸ isunsubstituted alkynyl. In certain embodiments, R⁷ is H; and R⁸ is C₁₋₆alkynyl. In certain embodiments, R⁷ is H; and R⁸ is ethynyl. In certainembodiments, R⁷ is H; and R⁸ is substituted aryl. In certainembodiments, R⁷ is H; and R⁸ is unsubstituted aryl. In certainembodiments, R⁷ is H; and R⁸ is substituted phenyl. In certainembodiments, R⁷ is H; and R⁸ is unsubstituted phenyl. In certainembodiments, R⁷ is H; and R⁸ is substituted heteroaryl. In certainembodiments, R⁷ is H; and R⁸ is unsubstituted heteroaryl. In certainembodiments, R⁷ is H; and R⁸ is substituted pyridyl. In certainembodiments, R⁷ is H; and R⁸ is unsubstituted pyridyl. In certainembodiments, R⁷ is H; and R⁸ is —OR^(e). In certain embodiments, R⁷ isH; and R⁸ is —O-aryl. In certain embodiments, R⁷ is H; and R⁸ is —OPh.In certain embodiments, R⁷ is H; and R⁸ is —O—C₁₋₆ alkyl. In certainembodiments, R⁷ is H; and R⁸ is —OH. In certain embodiments, R⁷ is H;and R⁸ is —N(R^(e))₂. In certain embodiments, R⁷ is H; and R⁸ is —N(C₁₋₆alkyl)₂. In certain embodiments, R⁷ is H; and R⁸ is —NH₂. In certainembodiments, R⁷ is H; and R⁸ is —C(═O)OR^(e). In certain embodiments, R⁷is H; and R⁸ is —C(═O)OMe. In certain embodiments, R⁷ is H; and R⁸ is—C(═O)OEt.

In certain embodiments, R⁸ is H; and R⁷ is substituted alkyl. In certainembodiments, R⁸ is H; and R⁷ is unsubstituted alkyl. In certainembodiments, R⁸ is H; and R⁷ is C₁₋₆ alkyl. In certain embodiments, R⁸is H; and R⁷ is methyl. In certain embodiments, R⁸ is H; and R⁷ isethyl. In certain embodiments, R⁸ is H; and R⁷ is propyl. In certainembodiments, R⁸ is H; and R⁷ is butyl. In certain embodiments, R⁸ is H;and R⁷ is substituted alkenyl. In certain embodiments, R⁸ is H; and R⁷is unsubstituted alkenyl. In certain embodiments, R⁸ is H; and R⁷ isC₁₋₆ alkenyl. In certain embodiments, R⁸ is H; and R⁷ is vinyl. Incertain embodiments, R⁸ is H; and R⁷ is allyl. In certain embodiments,R⁸ is H; and R⁷ is 4-butenyl. In certain embodiments, R⁸ is H; and R⁷ issubstituted alkynyl. In certain embodiments, R⁸ is H; and R⁷ isunsubstituted alkynyl. In certain embodiments, R⁸ is H; and R⁷ is C₁₋₆alkynyl. In certain embodiments, R⁸ is H; and R⁷ is ethynyl. In certainembodiments, R⁸ is H; and R⁷ is substituted aryl. In certainembodiments, R⁸ is H; and R⁷ is unsubstituted aryl. In certainembodiments, R⁸ is H; and R⁷ is substituted phenyl. In certainembodiments, R⁸ is H; and R⁷ is unsubstituted phenyl. In certainembodiments, R⁸ is H; and R⁷ is substituted heteroaryl. In certainembodiments, R⁸ is H; and R⁷ is unsubstituted heteroaryl. In certainembodiments, R⁸ is H; and R⁷ is substituted pyridyl. In certainembodiments, R⁸ is H; and R⁷ is unsubstituted pyridyl. In certainembodiments, R⁸ is H; and R⁷ is —OR^(e). In certain embodiments, R⁸ isH; and R⁷ is —O-aryl. In certain embodiments, R⁸ is H; and R⁷ is —OPh.In certain embodiments, R⁸ is H; and R⁷ is —O—C₁₋₄ alkyl. In certainembodiments, R⁸ is H; and R⁷ is —OH. In certain embodiments, R⁸ is H;and R⁷ is —N(R^(e))₂. In certain embodiments, R⁸ is H; and R⁷ is —N(C₁₋₆alkyl)₂. In certain embodiments, R⁸ is H; and R⁷ is —NH₂. In certainembodiments, R⁸ is H; and R⁷ is —C(═O)OR^(e). In certain embodiments, R⁸is H; and R⁷ is —C(═O)OMe. In certain embodiments, R⁸ is H; and R⁷ is—C(═O)OEt.

In certain embodiments, R⁷ and R⁸ are each H.

In certain embodiments, R⁹ and R¹⁰ are each independently selected fromthe group consisting of substituted alkyl, unsubstituted alkyl,substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, andunsubstituted alkynyl. In certain embodiments, R⁹ and R¹⁰ are eachindependently selected from the group consisting of substituted alkyland unsubstituted alkyl. In certain embodiments, R⁹ and R¹⁰ are eachC₁₋₆ alkyl. In certain embodiments, R⁹ and R¹⁰ are each methyl. Incertain embodiments, R⁹ and R¹⁰ are each independently selected from thegroup consisting of methyl, ethyl, propyl, and butyl.

In certain embodiments, R⁹ is optionally substituted alkyl; and R¹⁰ isoptionally substituted aryl. In certain embodiments, R⁹ is optionallysubstituted alkyl; and R¹ is optionally substituted phenyl. In certainembodiments, R⁹ is C₁₋₄ alkyl; and R¹⁰ is optionally substituted aryl.In certain embodiments, R⁹ is C₁₋₆ alkyl; and R¹⁰ is optionallysubstituted phenyl. In certain embodiments, R⁹ is methyl; and R¹⁰ isphenyl. In certain embodiments, R¹⁰ is optionally substituted alkyl; andR⁹ is optionally substituted aryl. In certain embodiments, R¹⁰ isoptionally substituted alkyl; and R⁹ is optionally substituted phenyl.In certain embodiments, R¹⁰ is C₁₋₆ alkyl; and R⁹ is optionallysubstituted aryl. In certain embodiments, R¹⁰ is C₁₋₆ alkyl; and R⁹ isoptionally substituted phenyl. In certain embodiments, R¹⁰ is methyl;and R⁹ is phenyl.

In certain embodiments, R⁹ is H; and R¹⁰ is substituted alkyl. Incertain embodiments, R⁹ is H; and R¹⁰ is unsubstituted alkyl. In certainembodiments, R⁹ is H; and R¹⁰ is C₁₋₆ alkyl. In certain embodiments, R⁹is H; and R¹⁰ is methyl. In certain embodiments, R⁹ is H; and R¹⁰ isethyl. In certain embodiments, R⁹ is H; and R¹⁰ is propyl. In certainembodiments, R⁹ is H; and R¹⁰ is butyl. In certain embodiments, R⁹ is H;and R¹⁰ is substituted alkenyl. In certain embodiments, R⁹ is H; and R¹⁰is unsubstituted alkenyl. In certain embodiments, R⁹ is H; and R¹⁰ isC₁₋₆ alkenyl. In certain embodiments, R⁹ is H; and R¹⁰ is vinyl. Incertain embodiments, R⁹ is H; and R¹⁰ is allyl. In certain embodiments,R⁹ is H; and R¹⁰ is 4-butenyl. In certain embodiments, R⁹ is H; and R¹⁰is substituted alkynyl. In certain embodiments, R⁹ is H; and R¹⁰ isunsubstituted alkynyl. In certain embodiments, R⁹ is H; and R¹⁰ is C₁₋₆alkynyl. In certain embodiments, R⁹ is H; and R¹⁰ is ethynyl. In certainembodiments, R⁹ is H; and R¹⁰ is substituted aryl. In certainembodiments, R⁹ is H; and R¹⁰ is unsubstituted aryl. In certainembodiments, R⁹ is H; and R¹⁰ is substituted phenyl. In certainembodiments, R⁹ is H; and R¹⁰ is unsubstituted phenyl. In certainembodiments, R⁹ is H; and R¹⁰ is substituted heteroaryl. In certainembodiments, R⁹ is H; and R¹⁰ is unsubstituted heteroaryl. In certainembodiments, R⁹ is H; and R¹⁰ is substituted pyridyl. In certainembodiments, R⁹ is H; and R¹⁰ is unsubstituted pyridyl. In certainembodiments, R⁹ is H; and R¹⁰ is —OR^(e). In certain embodiments, R⁹ isH; and R¹⁰ is —O-aryl. In certain embodiments, R⁹ is H; and R¹⁰ is —OPh.In certain embodiments, R⁹ is H; and R¹⁰ is —O—C₁₋₆ alkyl. In certainembodiments, R⁹ is H; and R¹⁰ is —OH. In certain embodiments, R⁹ is H;and R¹⁰ is —N(R^(e))₂. In certain embodiments, R⁹ is H; and R¹⁰ is—N(C₁₋₆ alkyl)₂. In certain embodiments, R⁹ is H; and R¹⁰ is —NH₂. Incertain embodiments, R⁹ is H; and R¹⁰ is —C(═O)OR^(e). In certainembodiments, R⁹ is H; and R¹⁰ is —C(═O)OMe. In certain embodiments, R⁹is H; and R¹⁰ is —C(═O)OEt.

In certain embodiments, R¹⁰ is H; and R⁹ is substituted alkyl. Incertain embodiments, R¹⁰ is H; and R⁹ is unsubstituted alkyl. In certainembodiments, R¹⁰ is H; and R⁹ is C₁₋₆ alkyl. In certain embodiments, R¹⁰is H; and R⁹ is methyl. In certain embodiments, R¹⁰ is H; and R⁹ isethyl. In certain embodiments, R¹⁰ is H; and R⁹ is propyl. In certainembodiments, R¹⁰ is H; and R⁹ is butyl. In certain embodiments, R¹⁰ isH; and R⁹ is substituted alkenyl. In certain embodiments, R¹⁰ is H; andR⁹ is unsubstituted alkenyl. In certain embodiments, R¹⁰ is H; and R⁹ isC₁₋₆ alkenyl. In certain embodiments, R¹⁰ is H; and R⁹ is vinyl. Incertain embodiments, R¹⁰ is H; and R⁹ is allyl. In certain embodiments,R¹⁰ is H; and R⁹ is 4-butenyl. In certain embodiments, R¹⁰ is H; and R⁹is substituted alkynyl. In certain embodiments, R¹⁰ is H; and R⁹ isunsubstituted alkynyl. In certain embodiments, R¹⁰ is H; and R⁹ is C₁₋₆alkynyl. In certain embodiments, R¹⁰ is H; and R⁹ is ethynyl. In certainembodiments, R¹⁰ is H; and R⁹ is substituted aryl. In certainembodiments, R¹⁰ is H; and R⁹ is unsubstituted aryl. In certainembodiments, R¹⁰ is H; and R⁹ is substituted phenyl. In certainembodiments, R¹⁰ is H; and R⁹ is unsubstituted phenyl. In certainembodiments, R¹⁰ is H; and R⁹ is substituted heteroaryl. In certainembodiments, R¹⁰ is H; and R⁹ is unsubstituted heteroaryl. In certainembodiments, R¹⁰ is H; and R⁹ is substituted pyridyl. In certainembodiments, R¹⁰ is H; and R⁹ is unsubstituted pyridyl. In certainembodiments, R¹⁰ is H; and R⁹ is —OR^(e). In certain embodiments, R¹⁰ isH; and R⁹ is —O-aryl. In certain embodiments, R¹⁰ is H; and R⁹ is —OPh.In certain embodiments, R¹⁰ is H; and R⁹ is —O—C₁₋₆ alkyl. In certainembodiments, R¹⁰ is H; and R⁹ is —OH. In certain embodiments, R¹⁰ is H;and R⁹ is —N(R^(e))₂. In certain embodiments, R¹⁰ is H; and R⁹ is—N(C₁₋₆ alkyl)₂. In certain embodiments, R¹⁰ is H; and R⁹ is —NH₂. Incertain embodiments, R¹⁰ is H; and R⁹ is —C(═O)OR^(e). In certainembodiments, R¹⁰ is H; and R⁹ is —C(═O)OMe. In certain embodiments, R¹⁰is H; and R⁹ is —C(═O)OEt.

In certain embodiments, R⁹ and R¹⁰ are each H.

In certain embodiments, R⁷, R⁸, R⁹, and R¹⁰ are each H.

Compounds of Formula (G) include a ligand Y bound to the Fe^(II) atom. Ymay be any ligand capable of binding to the Fe^(II) atom to form acoordination complex. In certain embodiments, Y is a compound includingone or more electron donating moieties. In certain embodiments, Y acompound including one or more heteroatoms. In certain embodiments, Y isa solvent. In certain embodiments, Y is N(R^(f))₃. In certainembodiments, Y is NEt₃. In certain embodiments, Y is (i-Pr)₂NEt. Incertain embodiments, Y is R^(f)—O—R^(f). In certain embodiments, Y isR^(f)—O—R^(f); and each occurrence of R^(f) is independently optionallysubstituted alkyl. In certain embodiments, Y is R^(f)—O—R^(f); and eachoccurrence of R^(f) is independently C₁₋₆ alkyl. In certain embodiments,Y is diethyl ether. In certain embodiments, Y is methyl t-butyl ether.In certain embodiments, Y is R^(f)—S—R^(f). In certain embodiments, Y isdimethyl sulfide. In certain embodiments, Y is diethyl sulfide. Incertain embodiments, Y is substituted heterocyclyl. In certainembodiments, Y is unsubstituted heterocyclyl. In certain embodiments, Yis substituted tetrahydrofuran. In certain embodiments, Y is2-methyltetrahydrofuran. In certain embodiments, Y is unsubstitutedtetrahydrofuran. In certain embodiments, Y is substitutedtetrahydropyran. In certain embodiments, Y is unsubstitutedtetrahydropyran. In certain embodiments, Y is substituted heteroaryl. Incertain embodiments, Y is unsubstituted heteroaryl. In certainembodiments, Y is substituted pyridine. In certain embodiments, Y is2,6-lutidine. In certain embodiments, Y is unsubstituted pyridine.

In certain embodiments, R^(f) is substituted alkyl. In certainembodiments, R^(f) is unsubstituted alkyl. In certain embodiments, R^(f)is C₁₋₆ alkyl. In certain embodiments, R^(f) is methyl. In certainembodiments, R^(f) is ethyl. In certain embodiments, R^(f) is propyl. Incertain embodiments, R^(f) is butyl. In certain embodiments, R^(f) isAd. In certain embodiments, R^(f) is substituted alkenyl. In certainembodiments, R^(f) is unsubstituted alkenyl. In certain embodiments,R^(f) is vinyl. In certain embodiments, R^(f) is substituted alkynyl. Incertain embodiments, R^(f) is unsubstituted alkynyl. In certainembodiments, R^(f) is ethynyl. In certain embodiments, R^(f) issubstituted carbocyclyl. In certain embodiments, R^(f) is unsubstitutedcarbocyclyl. In certain embodiments, R^(f) is cyclopropyl. In certainembodiments, R^(f) is cyclobutyl. In certain embodiments, R^(f) iscyclopentyl. In certain embodiments, R^(f) is cyclohexyl. In certainembodiments, R^(f) is cycloheptyl. In certain embodiments, R^(f) issubstituted heterocyclyl. In certain embodiments, R^(f) is unsubstitutedheterocyclyl. In certain embodiments, R^(f) is substituted aryl. Incertain embodiments, R^(f) is unsubstituted aryl. In certainembodiments, R^(f) is substituted phenyl. In certain embodiments, R^(f)is unsubstituted phenyl. In certain embodiments, R^(f) is substitutedheteroaryl. In certain embodiments, R^(f) is unsubstituted heteroaryl.In certain embodiments, R^(f) is substituted pyridyl. In certainembodiments, R^(f) is unsubstituted pyridyl.

Shown in FIG. 3 is a proposed mechanism for the intramolecular C—Hamination reaction of an azide R″CH(R′″)N₃ (e.g., R(CH₂)₄N₃), catalyzedby a Fe^(II)Cl(L)-dipyrromethene complex (e.g., 3A), to yield a

dipyrromethene complex

dipyrromethene complex). First, the Fe^(II)Cl(L)-dipyrromethene complexundergoes a ligand exchange to form radical imido intermediate 4. Theintermediate 4 abstracts a hydrogen atom intramolecularly from a C—Hmoiety of intermediate 4 to give rise to intermediate 5. Radicalrecombination furnishes the C—H amination product 6. The net effect ofthe reaction is the transfer of the nitrene group N: of R″CH(R′″)N:(e.g., R(CH₂)₄N:) to the C—H of R″CH(R′″)N. The mechanism for a similarreaction using compound 3B as the catalyst instead of 3A is similar toor the same as the mechanism described herein.

The acyclic secondary amines may be synthesized under any suitableconditions described herein.

Synthesis of Protected Cyclic Secondary Amines

The method of preparing a compound of Formula (II-1), or a salt orstereoisomer thereof, which is a coordination complex of a cyclicsecondary amine and ferrous compound, may further comprise the step of:

reacting the compound of Formula (II-1), or a salt or stereoisomerthereof, with Boc₂O to provide a compound of Formula (II-2-A), which isa Boc-protected cyclic secondary amine:

or a salt or stereoisomer thereof; wherein X, n, R⁷, R⁸, R⁹, and R¹⁰ areas defined herein.

Exemplary compounds of Formula (II-2-A) that can be prepared by theinventive methods include, but are not limited to:

and salts and stereoisomers thereof.

The method of preparing a compound of Formula (II-1), or a salt orstereoisomer thereof, which is a coordination complex of a cyclicsecondary amine and ferrous compound, may further comprise the step of:

reacting the compound of Formula (II-1), or a salt or stereoisomerthereof, with Fmoc-OSuc to provide a compound of Formula (II-2-B), whichis a Fmoc-protected cyclic secondary amine:

or a salt or stereoisomer thereof; wherein X, n, R⁷, R⁸, R⁹, and R¹⁰ areas defined herein.

The protected cyclic secondary amines may be synthesized under anysuitable conditions described herein.

Synthesis of Cyclic Secondary Amines

The method of preparing a compound of Formula (II-2-A) or (II-2-B), or asalt or stereoisomer thereof, which is a Boc- or Fmoc-protected cyclicsecondary amine, may further comprise the step of:

deprotecting the compound of Formula (II-2-A) or (II-2-B), or a salt orstereoisomer thereof, to provide a cyclic amine of Formula (II-3):

or a salt or stereoisomer thereof; wherein X, n, R⁷, R⁸, R⁹, and R¹⁰ areas defined herein.

The step of deprotecting a compound of Formula (II-2-A) or (II-2-B), ora salt or stereoisomer thereof, may also comprise deprotecting thecompound of Formula (II-2-A) or (II-2-B), or a salt or stereoisomerthereof, under suitable conditions to remove the protecting group. Thestep of deprotecting a compound of Formula (II-2-A), or a salt orstereoisomer thereof, may comprise increasing the temperature of thecompound of Formula (II-2-A), or a salt or stereoisomer thereof, aboveroom temperature. In certain embodiments, the temperature of thecompound of Formula (II-2-A), or a salt or stereoisomer thereof, isincreased to at least 100° C. In certain embodiments, the temperature ofthe compound of Formula (II-2-A), or a salt or stereoisomer thereof, isincreased to at least 150° C. In certain embodiments, the temperature ofthe compound of Formula (II-2-A), or a salt or stereoisomer thereof, isincreased to at least 200° C. In certain embodiments, the temperature ofthe compound of Formula (II-2-A), or a salt or stereoisomer thereof, isincreased to at least 250° C.

The suitable conditions in the step of deprotecting a compound ofFormula (II-2-A), or a salt or stereoisomer thereof, may be acidicconditions. In certain embodiments, the deprotection step comprisesreacting an acidic compound with the compound of Formula (II-2-A), or asalt or stereoisomer thereof, to remove the protecting group. In certainembodiments, the acidic compound is an inorganic acid. In certainembodiments, the inorganic acid is HCl. In certain embodiments, theinorganic acid is HBr. In certain embodiments, the inorganic acid is HI.In certain embodiments, the inorganic acid is HClO₄. In certainembodiments, the inorganic acid is HNO₃. In certain embodiments, theinorganic acid is H₂SO₄. In certain embodiments, the inorganic acid isH₃PO₄. In certain embodiments, the acidic compound is an organic acid.In certain embodiments, the organic acid is trifluoroacetic acid. Incertain embodiments, the organic acid is a sulfonic acid. In certainembodiments, the organic acid is methanesulfonic acid. In certainembodiments, the organic acid is trifluoromethanesulfonic acid. Incertain embodiments, the organic acid is p-toluenesulfonic acid. Incertain embodiments, the organic acid is benzenesulfonatic acid. Incertain embodiments, the acidic compound is a trialkylsilyl halide. Incertain embodiments, the trialkylsilyl halide is trimethylsilylchloride. In certain embodiments, the trialkylsilyl halide istrimethylsilyl bromide. In certain embodiments, the trialkylsilyl halideis trimethylsilyl iodide. In certain embodiments, the acidic compound istrimethylsilyl trifluoromethanesulfonate. In certain embodiments, theacidic compound is tetrabutylammonium fluoride. In certain embodiments,the acidic compound is a Lewis acid. In certain embodiments, the Lewisacid is boron trifluoride etherate.

The suitable conditions in the step of deprotecting a compound ofFormula (II-2-A) or (II-2-B), or a salt or stereoisomer thereof, may benucleophilic conditions. In certain embodiments, the deprotection stepcomprises reacting an nucleophilic compound with the compound of Formula(II-2-A) or (II-2-B), or a salt or stereoisomer thereof, to remove theprotecting group. In certain embodiments, the suitable conditions in thedeprotection step comprise use of a nucleophilic compound. In certainembodiments, the nucleophilic compound is alkyl lithium. In certainembodiments, the nucleophilic compound is LiMe. In certain embodiments,the nucleophilic compound is n-BuLi. In certain embodiments, thenucleophilic compound is sec-BuLi. In certain embodiments, thenucleophilic compound is t-BuLi. In certain embodiments, thenucleophilic compound is aryl lithium. In certain embodiments, thenucleophilic compound is LiPh. In certain embodiments, the nucleophiliccompound is a Grignard reagent. In certain embodiments, the nucleophiliccompound is MeMgCl, MeMgBr, or MeMgI. In certain embodiments, thenucleophilic compound is EtMgCl, EtMgBr, or EtMgI. In certainembodiments, the nucleophilic compound is PhMgCl, PhMgBr, or PhMgI. Incertain embodiments, the nucleophilic compound is TMSMgCl or TMSMgBr. Incertain embodiments, the nucleophilic compound is ammonia. In certainembodiments, the nucleophilic compound is ammonium hydroxide. In certainembodiments, the nucleophilic compound is a primary amine. In certainembodiments, the nucleophilic compound is methylamine, ethylamine,n-propylamine, isopropylamine, n-butylamine, n-pentylamine,n-hexylamine, cyclohexylamine, ethanolamine (i.e., 2-aminoethanol), Tris(i.e., 2-amino-2-hydroxymethyl-propane-1,3-diol), ethylenediamine,triethylenediamine, or aniline. In certain embodiments, the nucleophiliccompound is a secondary amine. In certain embodiments, the nucleophiliccompound is dimethylamine, diethylamine, di-n-propylamine,diisopropylamine, ethylisopropylamine, dicyclohexylamine,methylethanolamine, pyrrolidine, piperidine, morpholine, piperazine, or1,4-bis-(3-aminopropyl)piperazine. In certain embodiments, thenucleophilic compound is a tertiary amine. In certain embodiments, thenucleophilic compound is trimethylamine, triethylamine,diisopropylethylamine (DIPEA), tri-n-butylamine, 4-dimethylaminopyridine(DMAP), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

The suitable conditions in the step of deprotecting a compound ofFormula (II-2-B), or a salt or stereoisomer thereof, may be basicconditions. In certain embodiments, the deprotection step comprisesreacting an basic compound with the compound of Formula (II-2-B), or asalt or stereoisomer thereof, to remove the protecting group. In certainembodiments, the suitable conditions in the deprotection step compriseuse of a basic compound. In certain embodiments, the basic compound isalkyl lithium. In certain embodiments, the basic compound is LiMe. Incertain embodiments, the basic compound is n-BuLi. In certainembodiments, the basic compound is sec-BuLi. In certain embodiments, thebasic compound is t-BuLi. In certain embodiments, the basic compound isaryl lithium. In certain embodiments, the basic compound is LiPh. Incertain embodiments, the basic compound is a Grignard reagent. Incertain embodiments, the basic compound is MeMgCl, MeMgBr, or MeMgI. Incertain embodiments, the basic compound is EtMgCl, EtMgBr, or EtMgI. Incertain embodiments, the basic compound is PhMgCl, PhMgBr, or PhMgI. Incertain embodiments, the basic compound is TMSMgCl or TMSMgBr. Incertain embodiments, the basic compound is ammonia. In certainembodiments, the basic compound is ammonium hydroxide. In certainembodiments, the basic compound is a primary amine. In certainembodiments, the basic compound is methylamine, ethylamine,n-propylamine, isopropylamine, n-butylamine, n-pentylamine,n-hexylamine, cyclohexylamine, ethanolamine (i.e., 2-aminoethanol), Tris(i.e., 2-amino-2-hydroxymethyl-propane-1,3-diol), ethylenediamine,triethylenediamine, or aniline. In certain embodiments, the basiccompound is a secondary amine. In certain embodiments, the basiccompound is dimethylamine, diethylamine, di-n-propylamine,diisopropylamine, ethylisopropylamine, dicyclohexylamine,methylethanolamine, pyrrolidine, piperidine, morpholine, piperazine, or1,4-bis-(3-aminopropyl)piperazine. In certain embodiments, the basiccompound is a tertiary amine. In certain embodiments, the basic compoundis trimethylamine, triethylamine, diisopropylethylamine (DIPEA),tri-n-butylamine, 4-dimethylaminopyridine (DMAP),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, or 2,6-lutidine.

The suitable conditions in the step of deprotecting a compound ofFormula (II-2-A) or (II-2-B), or a salt or stereoisomer thereof, may bereductive conditions. In certain embodiments, the deprotection stepcomprises reacting an reductive compound with the compound of Formula(II-2-A) or (II-2-B), or a salt or stereoisomer thereof, to remove theprotecting group. In certain embodiments, the suitable conditions in thedeprotection step comprise use of a reductive compound. In certainembodiments, the reductive compound is a mixture of zinc and HCl. Incertain embodiments, the reductive compound is LiAlH₄. In certainembodiments, the reductive compound is a mixture of rhodium andhydrogen. In certain embodiments, the reductive compound is a mixture ofsodium and ammonia.

The suitable conditions in the step of deprotecting a compound ofFormula (II-2-B), or a salt or stereoisomer thereof, may be oxidativeconditions. In certain embodiments, the deprotection step comprisesreacting an oxidative compound with the compound of Formula (II-2-B), ora salt or stereoisomer thereof, to remove the protecting group. Incertain embodiments, the oxidative compound is a mixture of CrO₃ andpyridine.

In certain embodiments, the compound of Formula (II-3) is of Formula(II-4):

or a stereoisomer thereof, wherein V is an anionic counterion. Allanionic counterions described herein are contemplated as being withinthe scope of the invention. In certain embodiments, the anioniccounterion is F⁻, Cl⁻, Br⁻, or I⁻. In certain embodiments, the anioniccounterion is ClO₄ ⁻. In certain embodiments, the anionic counterion isNO₃ ⁻. In certain embodiments, the anionic counterion is HSO₄ ⁻. Incertain embodiments, the anionic counterion is H₂PO₄ ⁻. In certainembodiments, the anionic counterion is a sulfonate ion. In certainembodiments, the anionic counterion is a methansulfonate,trifluoromethanesulfonate, p-toluenesulfonate, or benzenesulfonate ion.In certain embodiments, the anionic counterion is BF₄ ⁻.

A compound of Formula (II-4), or a stereoisomer thereof, may be furtherreacted by contacting with a base to provide a compound of Formula(II-3), or a stereoisomer thereof. In certain embodiments, the base isan inorganic base. In certain embodiments, the inorganic base isammonia. In certain embodiments, the inorganic base is ammoniumcarbonate. In certain embodiments, the inorganic base is ammoniumhydroxide. In certain embodiments, the inorganic base is an alkali metalcarbonate. In certain embodiments, the inorganic base is Li₂CO₃, Na₂CO₃,K₂CO₃, Rb₂CO₃, or Cs₂CO₃. In certain embodiments, the inorganic base isan alkali metal bicarbonate. In certain embodiments, the inorganic baseis LiHCO₃, NaHCO₃, KHCO₃, RbHCO₃, or CsHCO₃. In certain embodiments, theinorganic base is an alkali metal hydroxide. In certain embodiments, theinorganic base is LiOH, NaOH, KOH, RbOH, or CsOH. In certainembodiments, the inorganic base is an alkaline earth metal carbonate. Incertain embodiments, the inorganic base is BeCO₃, MgCO₃, CaCO₃, SrCO₃,or BaCO₃. In certain embodiments, the inorganic base is an alkalineearth metal bicarbonate. In certain embodiments, the inorganic base isBe(HCO₃)₂, Mg(HCO₃)₂, Ca(HCO₃)₂, Sr(HCO₃)₂, or Ba(HCO₃)₂. In certainembodiments, the inorganic base is an alkaline earth metal hydroxide. Incertain embodiments, the inorganic base is Be(OH)₂, Mg(OH)₂, Ca(OH)₂,Sr(OH)₂, or Ba(OH)₂. In certain embodiments, the base is an organicbase. In certain embodiments, the organic base is an aliphatic amine. Incertain embodiments, the organic base is an aromatic amine. In certainembodiments, the organic base is a primary amine. In certainembodiments, the organic base is a secondary amine. In certainembodiments, the organic base is a tertiary amine. In certainembodiments, the organic base is triethylamine, DIPEA, or DBU. Incertain embodiments, the organic base is substituted pyridine. Incertain embodiments, the organic base is 2,6-lutidine or DMAP. Incertain embodiments, the organic base is unsubstituted pyridine.

A compound of Formula (II-3), or a stereoisomer thereof, may be furtherreacted with an acid to provide a salt of compound of Formula (II-3), ora stereoisomer thereof. The acid is as described herein.

The cyclic secondary amines may be synthesized under any suitableconditions described herein.

The compounds synthesized by the inventive methods may be screened for awide range of biological activities, e.g., for anti-proliferative,anti-microbial, anti-arrhythmic, anti-hypertensive,anti-neurodegenerative, and/or anti-diabetic activities. The compoundsprepared by the inventive methods, or salts or stereoisomers thereof,may be administered to a subject to treat and/or prevent a disease(e.g., a proliferative disease, infectious disease, inflammatorydisease, autoimmune disease, cardiovascular disease, gastrointestinaldisease, neurodegenerative disease, or metabolic disease) in thesubject.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. These examples are forillustrative purposes only and are not to be construed as limiting thisinvention in any manner.

Preparation of the Iron-Based Catalysts

The iron-based catalysts described herein that are useful in theinventive methods (e.g., a ferrous compound of Formula (B) or (G), or asalt thereof, such as compounds 3A and 3B) may be synthesized accordingto reported processes, such as ones described in King et al., J. Am.Chem. Soc. 133, 4917 (2011), which is incorporated herein by reference.

Preparation of Acyclic Secondary Amines

Acyclic secondary amines (e.g., compounds 25A-25D) may be synthesizedaccording to the general method shown in Scheme 4 through a reaction ofan azide (e.g., R^(A)N₃) with an substituted or unsubstituted, branchedor unbranched, cyclic or acyclic olefin (e.g., compounds 26A-26C)catalyzed by a compound of Formula (B) or (G) (e.g., compound 3, 3A, or3B). Any suitable conditions may be employed. For example, compounds25A-25D may be prepared at about 25° C., about 60° C., about 100° C., orabout 120° C. for about 6 hours, about 12 hours, or about 24 hours,using benzene as the solvent or no solvent (i.e., neat). When 1 equiv.of R^(A)N₃ and 1 or more equiv. of the olefin are used, the loading ofcompound 3 may be about 10% (i.e., 0.1 equiv.) or about 20% (i.e., 0.2equiv.). The reactions may be conducted under an atmosphere of nitrogenor argon. Compounds 25A-25D may be purified and characterized usingmethods known in the art (e.g., flash chromatography).

For example, a wide range of acyclic secondary amines may be prepared bya method similar to the following procedure. Under an inert N₂atmosphere, 1-azidoadamantane (60.9 mg, 0.28 mmol, 10 equiv.) was addedto a stirring solution of compound 3B (20 mg, 0.028 mmol, 1 equiv.) in 1mL of an olefin (e.g., styrene) in a 20 mL scintillation vial. Theresultant inky, dark red solution was stirred for 12 hours at 25° C. Themixture was purified by flash chromatography using a short pipette oftriethylamine-treated silica gel eluted with 10:1 hexanes:EtOAc to yielda brightly colored solution. Volatiles were removed under reducedpressure to yield the acyclic secondary amine product. The yields weredetermined by ¹H NMR via integration against ferrocene, averaging overthree runs for each substrate.

Alternatively, the following procedure may be used to make acyclicsecondary amines, especially, allylic acyclic secondary amines. Under aninert N₂ atmosphere, 1-azidoadamantane (30.5 mg, 0.14 mmol, 5 equiv., or60.9 mg, 0.28 mmol, 10 equiv.) was added to a stirring solution ofcompound 3B (20 mg, 0.028 mmol, 1 equiv.) in 2 mL of an olefin in a 20mL scintillation vial. The resultant inky, dark red solution was stirredfor 12 hours at the indicated temperature. The mixture was concentratedand purified by flash chromatography eluted with 9:1 DCM:methanol toyield a yellow solution. Volatiles were removed under reduced pressureto yield the allylic amine product. The yields were determined by ¹H NMRvia integration against ferrocene.

Yields of exemplary acyclic secondary amines synthesized using theinventive methods are shown in Table 5.

TABLE 5 Synthesis of acyclic amines 25.

3B Temperature 26 Loading (mol %) (° C.) 25 Yield E/Z ratio

10 100

49

20 20 10  25  60 100

35 51 53

20 10  25 100

26 38 Only E isomer observed

20 10  25 100

12 29

20 20 10  25  60 100

10 38 39

10 100

14

10 100

17

20 20 10 10  25  60 100 120

23 50 48 25 5:1 E:Z 6:1 E:Z 6:1 E:Z 3:1 E:Z

20 10  60 100

68 49 7:1 E:Z 5:1 E:Z

20 10  60 100

71 57 5:1 E:Z 4:1 E:Z

10  60

17Preparation of Protected Cyclic Secondary Amines

Boc- or Fmoc-protected cyclic secondary amines may be synthesizedaccording to the general method shown in Scheme 5.

For example, a variety of substituted aliphatic azides (e.g.,1-azido-5-hexene) were subjected to compound 3A. Exposure of1-azido-5-hexene to compound 3A at room temperature in benzene quicklyconsumed the azide, as ascertained by the disappearance of the azidestretch in the IR spectrum and afforded a new paramagnetically shifted¹H NMR spectrum. Crystallization was induced by slow diffusion of ahexanes solution of the product at 23° C. to yield crystals in which2-vinylpyrrolidine was bound to the iron-based complex to give compound8 (Scheme 6 and FIG. 5A). Similarly, treatment of 1-azido-4-phenylbutanewith 3A afforded the cyclized product 2-phenylpyrrolidine as aniron-bound adduct 9 (FIG. 5B). In addition to allylic and benzylic C—Hbonds, less reactive tertiary C—H bonds could similarly befunctionalized. The reaction of 1-azido-5-methylpentane and 3A understandard conditions gave the 2,2-dimethylpyrrolidine iron-bound product.Gratifyingly, even secondary aliphatic C—H bonds could be functionalizedthrough this method. Addition of 1-azidohexane to 3A resulted in therapid consumption of the azide to afford a single product, which wasdetermined to be the 2-ethylpyrrolidine complex 10 (FIG. 5C). In anattempt to activate the primary C—H bond of an aliphatic azidesubstrate, 1-azidobutane was exposed to 3A. However, the only productsobserved in this transformation were linear n-butylamine andn-butylimine. To eliminate the potential for imine formation, through aprocess involving intermolecular C—H bond activation or β-hydrideelimination, the gem-dimethyl substrate 2-azido-2-methylpentane wasprepared and subjected to 3A at room temperature for 6 h to afford thecyclized 2,2-dimethylpyrrolidine complex 11 (FIG. 5D) in quantitativeyield. The presence of the two α-Me substituents may facilitate the C—Hbond functionalization/cyclization process through the Thorpe-Ingoldeffect (Beesley et al., J. Chem. Soc., Trans., 107, 1080 (1915)).

With a reliable protocol for the stoichiometric C—Hfunctionalization/cyclization of aliphatic azides in hand, attempts torender the reaction catalytic were undertaken (5-10 equiv. of azide per1 equiv. of compound 3A or 3B). Unfortunately, examination of thecyclization reaction under catalytic conditions did not markedlyincrease the yield of the resultant free heterocyclic product. The lackof catalyst turnover may be attributed to product inhibition, in which atight Lewis-acid/base pair between the dipyrromethene-iron and theheterocyclic nitrogen atom is formed. This hypothesis is supported bythe ease with which crystals of the corresponding dipyrromethene-ironcomplexes were obtained (FIGS. 4 and 5).

To overcome this problem, the cyclization reaction was performed in thepresence of an in situ protection reagent, which would reduce thenucleophilicity of the product cyclic amines while avoiding thegeneration of byproducts that might retard or prevent catalysis.Accordingly, treatment of a solution of 1-azido-4-phenylbutane and9-fluorenylmethyl N-succinimidyl carbonate (Fmoc-OSuc) in benzene atroom temperature with a stoichiometric amount of compound 3A for 12 hafforded the Fmoc-protected 2-phenylpyrrolidine in 98% yield. Similarly,addition of an equivalent of compound 3A to a solution of1-azido-4-phenylbutane and di-t-butyl dicarbonate (Boc₂O) under similarreaction conditions afforded the 1-butyloxycarbonyl (Boc) protectedproduct 1-Boc-2-phenylpyrrolidine in 93% yield. As catalyst loading wasdecreased, it was discovered that the N-hydroxysuccinimide byproduct ofFmoc-protection led to catalyst decomposition through ligand protonationand limited the reaction to a single turnover. Fortunately, thebyproducts of protection with Boc₂O (i.e., t-BuOH and CO₂) did notinhibit catalyst turnover, permitting the cyclic amines to besynthesized with catalytic amounts of compound 3B (chosen to eliminatebenzylic C—H bonds from catalyst meso-aryl substituent).

Application of catalytic quantities of compound 3B to the established insitu protection protocol for C—H functionalization/cyclization wasinvestigated (Table 2). Exposure of azides 13 containing allylic,benzylic, or tertiary C—H bonds to compound 3B (10 mol %) provided thecorresponding Boc-protected pyrrolidine 14 in good yield (57-64%,entries 1-3). Next, catalytic functionalization of a secondary C—H bondwas also possible, affording 1-Boc-2-ethylpyrrolidine in modest yield(27%, entry 4). Even, a primary C—H bond in 2-azido-2-methylpentanecould be functionalized to give 1-Boc-2,2-dimethylpyrrolidine in 17%yield (entry 6). The substrate scope was then expanded to includehetero-atom containing functional groups. Exposure ofethyl-5-azidopentanoate to compound 3B under standard catalyticconditions only resulted in linear primary amine and imine products(entry 7). Again, blocking the α-position of the azide 13 withgem-dimethyl substituents led to productive cyclization (entry 8).Introduction of heteroatoms between the reactive functionalities allowedfor the formation of 1-Boc-2-phenyloxazolidine in 47% yield (entry 9).

TABLE 2 Amination reactions of azides 13 catalyzed by compound 3Byielding pyrrolidines 14.

Yield Entry 13 14 (%)^(a) 1

64 2

57 3

60 4

27 5

 0 6

17 (7)^(b) 7

 0 8

11^(b) 9

47^(b) ^(a)Yield determined by ¹H NMR using ferrocene ortrimethoxybenzene as the internal standard. ^(b)20 mol% loading ofcompound 3B.

The scope of C—H functionalization/cyclization was further explored insubstrates accessible via cuprate-assisted epoxide opening (Drouin etal., Tetrahedron 36, 1195 (1980)) followed by azide formation (Table 3).The use of epoxides 15 and alkyl halides (which may be transformed intoGrignard reagents 16) permits virtually any substitution pattern to beprogrammed into the ensuing heterocyclic product. After Li₂[CuCl₄]promoted epoxide opening, the resultant primary or secondary alcoholswere tosylated and displaced with sodium azide to provide the desiredcyclization precursor 17. Alternatively, tertiary and benzylic alcoholswere directly converted to the corresponding azide (e.g., compound 18)by exposure to trimethylsilylazide and boron trifluoride diethyletherate (Mukaiyama et al., Heterocycles 80, 63 (2010)). Allylic,tertiary and secondary C—H bond substrates available through eitherreaction sequence underwent facile C—H functionalization/cyclization togive protected (e.g., protected with Boc) cyclic amines 19 (entries 1-9,58-98% yield). Notably, this method provides access to an all-carbonspiro-center (entry 7, 67%). Functionalization of primary C—H bonds mayrequire a higher loading of the catalyst (e.g., compound 3A or 3B) thana catalytic amount (entry 10). For example, a stoichiometric reactionsimilar to the reaction in Table 3, entry 10, except that Fmoc-OSuc wasused instead of Boc₂O and that 1 equiv. of compound 3B was employed,gave rise to

in 78% yield. Interestingly, use of (R)-2-phenyl-5-azidopentane (95%enantiomeric excess (ee)) in the catalytic transformation resulted in(S)-2-methyl-2-phenylpyrrolidine with retention of configuration (entry5, 75%, 93% ee). A similar reaction using stoichiometric quantities ofcompound 3A gave the corresponding (S)-2-methyl-2-phenylpyrrolidineiron-bound adduct 20 whose absolute stereochemistry was verified byX-ray diffraction (FIG. 6).

TABLE 3 Synthesis of 1,2,3,4-substituted pyrrolidines 19.

Yield Entry 15 16 17 or 18 19^(a) (%)^(b) dr^(c) 1

60 3.9:1 2

66 1.5:1 3

70 4

98 5

75 6

84 1.1:1 7

67 8

73 2.1:1 9

58 5.5:1.5:1:0.08 10

14 ^(a)Pyrrolidines 19 are racemic unless otherwise noted. ^(b)Yieldsare representative of cyclization reactions only and are determined by¹H NMR using ferrocene or trimethoxybenzene as the internal standard.^(c)The term “dr” refers to diastereomeric ratio.

The potential of the inventive methods to generate cyclic amines ofvarious ring sizes was also explored. It was expected that a vinyldirecting group could be employed to encourage the site-selectivefunctionalization of the allylic C—H bond within the acyclic precursor.Treatment of 1-azido-6-heptene and Boc₂O (1 equiv.) with compound 3B (1equiv.) at room temperature generated the 6-membered1-Boc-2-vinylpiperidine (entry 1, Table 4) as the exclusive reactionproduct. Unfortunately, use of the vinyl activating group to target7-membered azepane products led to exclusive formation of thecorresponding pyrrolidine (entry 4). In contrast, a phenyl activatinggroup was not effective in favoring the formation of a 6-membered ringproduct. Addition of compound 3B to 1-azido-5-phenyl-pentane understandard conditions resulted in a 1:0.85 mixture of both1-Boc-2-phenylpiperidine and 1-Boc-2-benzylpyrrolidine (entry 2).Similarly, the use of a tertiary C—H bond to favor 6-membered ringformation in the case of 1-azido-5-methylhexane resulted in a mixture ofpiperidine and pyrrolidine products (entry 3). An attempt was made toblock the potential for pyrrolidine formation; exposure of2-azido-2,5,5-trimethylhexane and Fmoc-OSuc to compound 3B resulted inboth the anticipated 1-Fmoc-2,2,5,5-tetramethylpiperidine and theunexpected 1-Fmoc-2,2-dimethyl-4-tert-butylazetidine (entry 5).Alternatively, use of compound 3A and omission of Fmoc-OSuc allowed forthe characterization of the corresponding iron-bound adducts by X-rayanalysis (FIGS. 7B and 7C).

TABLE 4 Synthesis of cyclic amines 24 of various ring sizes.

Entry Azide 23 Product(s) 24 Conv. (%)^(a,b) 1

45 2

82 3

52 (1.0:0.9) 4

47 (1.0:1.5) 5

47 (1.0:1.5) ^(a)Yields are determined by ¹H NMR using ferrocene ortrimethoxybenzene as the internal standard. ^(b)Ratios are detereminedby integration of GC/MS peaks.

As illustrated in FIG. 3, it is hypothesize that the C—H bondfunctionalization/cyclization reaction occurs via a three-step processinvolving: (1) oxidation of the Fe^(II) catalyst (e.g., compound 3A) toan Fe^(III) imido radical (e.g., compound 4) by the alkyl azidesubstrate; (2) intramolecular H-atom abstraction to generate an alkylradical and an Fe^(III) amide (e.g., compound 5) (path Ia); and (3)radical recombination to form the observed cyclic amine product (e.g.,compound 6) (path Ib). Alternatively, a direct C—H bond insertion by theFe^(III) imido radical intermediate cannot be excluded (path II). Bothmechanisms require that the substrate C—H bond be brought into closeproximity to the reactive Fe-imido radical. Based on previous findings,the imido radical likely resides in the plane defined by the iron andthe dipyrrin ligand, flanked by large pyrrolide adamantyl substituents.Such a conformation requires that the C—H bond substrate approach theimido radical opposite the chloride ligand. It is expected that oncethis orientation is obtained, C—H bond functionalization is rapid. Thishypothesis is supported by the retention of stereochemical informationduring the cyclization of (R)-2-phenyl-5-azidopentane. Additionally,cyclization of 1-azido-4-deutero-4-phenylbutane (Scheme 7) provides anintramolecular kinetic isotope effect (KIE) of 5.3 at 25° C. and 5.1(2)at 65° C. This value is similar to the KIE observed in the hydroxylationof 1,3-dideuteroadamantane catalyzed by tetramesitylporphyrin iron withoxone [k_(H)/k_(D)=4.1(2)](Sorokin et al., J. Am. Chem. Soc. 115, 7293(1993)). Finally, addition of the radical clock substrate(2-(4-azidobutyl)cyclopropyl)benzene to compound 3B exclusivelyfurnishes the pyrrolidine product1-Boc-2-(2-phenylcyclopropyl)pyrrolidine with the cyclopropyl unitintact (Scheme 8). The non-unity intramolecular kinetic isotope effectsuggests a stepwise mechanism for benzylic substrates (FIG. 3, Path I(i.e., Ia and Ib)), which is consistent with previously reportedintermolecular amination reaction (King et al., J. Am. Chem. Soc. 133,4917 (2011)). The stereospecificity of the cyclization and thepreservation of the cyclopropyl unit in the radical clock experimentsuggest that if a stepwise mechanism is operative, the radicalintermediate following H-atom abstraction is short-lived [recombinationrate>1011 s⁻¹ (Newcomb et al., Acc. Chem. Res. 33, 449 (2000))].Alternatively, the reaction mechanism may change to a direct insertionmechanism (FIG. 3, path II) when stronger substrate C—H bonds arefunctionalized.

The results described herein have demonstrated the oxidative potency ofthe transiently formed, high-spin iron imido radical for thefunctionalization of both activated and unactivated aliphatic C—H bondsubstrates. This iron-mediated cyclization of linear azides providesfacile entry into complex acyclic and cyclic amines from readilyavailable substrates that cannot be achieved by azide photolysis (Bartonet al., J. Chem. Soc. 2444 (1965)) or via classicHoffmann-Löffler-Freytag methodologies (Hoffman, Berichte 18, 105(1885)). It is expected that the methods of the invention can beextended to produce a wide variety of acyclic and cyclic amines (e.g.,saturated cyclic amines). The oxidative amination of aliphatic C—H bondsover more electron-rich C—H bonds (olefins and aromatics) is madepossible by the unique electronic structure of the putativeiron-stabilized imido radical intermediate.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A method of preparing a compound of Formula (II-1):

or a salt thereof, the method comprising reacting an azide of Formula (F), or a salt thereof, with a ferrous compound of Formula (G), or a salt thereof:

wherein: W is selected from the group consisting of mesityl and 2,6-dichlorophenyl; each occurrence of X is independently selected from the group consisting of —O—, —S—, —NR^(c)—, and —C(R^(d))₂—; R^(c) is selected from the group consisting of hydrogen, a nitrogen protecting group, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; each one of R⁷, R⁸, R⁹, and R¹⁰, and each occurrence of R^(d), are independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(e), —N(R^(e))₂, —SR^(e), —CN, —C(═NR^(e))R^(e), —C(═NR^(e))OR^(e), —C(═NR^(e))N(R^(e))₂, —NO₂, —NR^(e)C(═O)R^(e), —NR^(e)C(═O)OR^(e), —NR^(e)C(═O)N(R^(e))₂, —OC(═O)R^(e), —OC(═O)OR^(e), —OC(═O)N(R^(e))₂, and —ON(R^(e))₂; each occurrence of R^(e) is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(e) groups are joined to form an optionally substituted heterocyclic ring; or two of R⁷, R⁸, R⁹, R¹⁰, R^(c), and R^(d) groups are joined to form an optionally substituted carbocyclyl or optionally substituted heterocyclic ring; Y is selected from the group consisting of N(R^(f))₃, R^(f)—O—R^(f), R^(f)—S—R^(f), optionally substituted heterocyclyl, and optionally substituted heteroaryl; each occurrence of R^(f) is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and n is 1, 2, 3, 4, or
 5. 2. The method of claim 1, further comprising reacting the compound of Formula (II-1), or a salt thereof, with di-t-butyl dicarbonate (Boc₂O) to provide a compound of Formula (II-2-A), or a salt thereof, or with 9-fluorenylmethyl N-succinimidyl carbonate (Fmoc-OSuc) to provide a compound of Formula (II-2-B), or a salt thereof:


3. The method of claim 2, further comprising deprotecting the compound of Formula (II-2-A) or (II-2-B), or a salt thereof, to provide a cyclic amine of Formula (II-3):

or a salt thereof.
 4. The method of claim 3, wherein the deprotection step comprises reacting an acidic compound, a nucleophilic compound, or a reductive compound with the compound of Formula (II-2-A), or a salt thereof, or reacting a nucleophilic compound, a basic compound, a reductive compound, or an oxidative compound with the compound of Formula (II-2-B), or a salt thereof, to provide the cyclic amine of Formula (II-3), or a salt thereof.
 5. The method of claim 1, wherein R⁷ and R⁸ are each hydrogen.
 6. The method of claim 1, wherein R⁷ is hydrogen; and R⁸ is optionally substituted alkyl.
 7. The method of claim 1, wherein R⁷ and R⁸ are each optionally substituted alkyl.
 8. The method of claim 1, wherein Y is R^(f)—O—R^(f); and each occurrence of R^(f) is independently optionally substituted alkyl.
 9. The method of claim 1, wherein Y is optionally substituted heterocyclyl.
 10. The method of claim 1, wherein Y is optionally substituted tetrahydrofuran or optionally substituted tetrahydropyran.
 11. The method of claim 1, wherein Y is optionally substituted heteroaryl.
 12. The method of claim 1, wherein Y is optionally substituted pyridine.
 13. The method of claim 1, wherein n is
 2. 14. The method of claim 1, wherein n is
 3. 15. The method of claim 1, wherein n is
 4. 16. The method of claim 1, wherein W is mesityl.
 17. The method of claim 1, wherein W is 2,6-dichlorophenyl.
 18. The method of claim 1, wherein Y is diethyl ether.
 19. The method of claim 1, wherein the ferrous compound of Formula (G) is of Formula (3A):


20. The method of claim 1, wherein the ferrous compound of Formula (G) is of Formula (3B): 